@article {pmid39241994,
year = {2024},
author = {Velumani, M and Thiruppathi, G and Mohankumar, A and Anila, PA and Hema, T and Sundararaj, P and Premasudha, P},
title = {Chitosan nanoparticles encapsulated Piper betle essential oil alleviates Alzheimer's disease associated pathology in Caenorhabditis elegans.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {135323},
doi = {10.1016/j.ijbiomac.2024.135323},
pmid = {39241994},
issn = {1879-0003},
abstract = {A multifaceted approach in treating Alzheimer's disease (AD), a neurodegenerative condition that poses health risks in the aging population is explored in this investigation via encapsulating Piper betle essential oil (PBEO) in chitosan nanoparticles (ChNPs) to improve solubility and efficacy of PBEO. PBEO-ChNPs mitigated AD-like features more effectively than free PBEO by delaying paralysis progression and reducing serotonin hypersensitivity, ROS levels, Aβ deposits, and neurotoxic Aβ-oligomers in the Caenorhabditis elegans AD model. PBEO-ChNPs significantly improved lifespan, neuronal health, healthspan, cognitive function, and reversed deficits in chemotaxis and reproduction. PBEO-ChNPs also induced stress response genes daf-16, sod-3, and hsp-16.2. The participation of the DAF-16 pathway in reducing Aβ-induced toxicity was confirmed by daf-16 RNAi treatment, and upregulation of autophagy genes leg-1, unc-51, and bec-1 was noted. This study is the first to demonstrate an alternative biopolymeric nanoformulation with natural PBEO and chitosan, in mitigating AD and its associated symptoms.},
}

@article {pmid39241972,
year = {2024},
author = {Luo, Y and Hu, B and Yuan, Z and Bi, H and Yu, J and Pan, Q},
title = {Emerging insights into traditional Chinese medicine associated with neurodegenerative diseases: a bibliometric analysis.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {118785},
doi = {10.1016/j.jep.2024.118785},
pmid = {39241972},
issn = {1872-7573},
abstract = {Research suggests that traditional Chinese medicine (TCM) holds promise in offering innovative approaches to tackle neurodegenerative disorders. In our endeavor, we conducted a comprehensive bibliometric analysis to delve into the landscape of TCM research within the realm of neurodegenerative diseases, aiming to uncover the present scenario, breadth, and trends in this field. This analysis presents potentially valuable insights for the clinical application of traditional Chinese medicine and provides compelling evidence supporting its efficacy in the treatment of neurodegenerative conditions.

AIM OF THE STUDY: The incidence of neurodegenerative diseases is on the rise, yet effective treatments are still lacking. Research indicates that TCM could offer novel perspectives for addressing neurodegenerative conditions. Nonetheless, the literature on this topic is intricate and multifaceted, with existing reviews offering only limited coverage. To gain a thorough understanding of TCM research in neurodegenerative diseases, we undertook a bibliometric analysis to explore the current status, scope, and trends in this area.

MATERIALS AND METHODS: A literature search was carried out on April 1, 2024, utilizing the Web of Science Core Collection (WoSCC). Visualization and quantitative analyses were then performed with the assistance of CiteSpace, VOSviewer, and R software.

RESULTS: A total of 6,856 articles were retrieved in the search. Research on TCM for neurodegenerative diseases commenced in 1989 and has exhibited a notable overall growth since then. Main research contributors include East Asian countries like China, as well as the United States. Through our analysis, we identified 15 highly productive authors, 10 top-tier journals, 13 citation clusters, 11 influential articles, and observed a progression in keyword evolution across 4 distinct categories. In 2020, there was a significant upsurge in the knowledge base, collaboration efforts, and publication output within the field. This field is interdisciplinary: network pharmacology emerges as the cutting-edge paradigm in TCM research, while Alzheimer's disease remains a prominent focus among neurodegenerative conditions due to its evolving etiology. A burst detection analysis unveils that in 2024, the focal points of research convergence between TCM and neurodegenerative diseases lie in two key biological processes or mechanisms: autophagy and microbiota.

CONCLUSIONS: For the first time, this study quantitatively and visually captures the evolution of TCM in addressing neurodegenerative diseases, showcasing a notable acceleration in recent years. Our findings underscore the pivotal role of interdisciplinary collaboration and the necessity for increased global partnerships. Network pharmacology, leveraging the advancements of the big data era, embraces a holistic and systematic approach as a novel paradigm in exploring traditional Chinese medicine and unraveling their fundamental mechanisms. Three ethnomedical plants-Tianma, Renshen, and Wuweizi-demonstrate the promise of their bioactive compounds in treating neurodegenerative disorders, bolstered by their extensive historical usage for such ailments. Moreover, our intricate analysis of the evolutionary trajectories of key themes such as targets and biomarkers substantially enriches our comprehension of the underlying mechanisms involved.},
}

@article {pmid39241971,
year = {2024},
author = {Xie, Z and Liu, W and Dang, R and Hu, X and Cai, F and Xiang, Z and Zhao, X and Cheng, X and Wang, C},
title = {Effects and mechanisms of harmine on ameliorating ethanol-induced memory impairment.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {118789},
doi = {10.1016/j.jep.2024.118789},
pmid = {39241971},
issn = {1872-7573},
abstract = {Peganum harmala L., a traditional Uyghur ethnic medicine widely used in China, is commonly used in the treatment of conditions such as hemiplegia, forgetfulness, cough, and asthma. Harmine and other β-carboline alkaloids, one of the main active ingredients in P. harmala, have exhibited various pharmacological activities, including anti-Alzheimer's, antidepressant, anti-inflammatory, and antioxidant effects. However, the effects and underlying mechanisms of harmine on improving ethanol-induced memory impairment remain unclear.

AIM OF THE STUDY: This study aimed to investigate the effects of harmine on ameliorating ethanol-induced memory impairment, and to explore potential mechanisms.

MATERIALS AND METHODS: Ethanol (30%, i.g.) was used to induce memory impairment model. The effect of harmine on memory impairment was evaluated by Morris water maze (MWM). The histopathological analysis, immunofluorescence staining, RT-qPCR and UHPLC-MS/MS methods were performed to further investigate the underlying mechanisms.

RESULTS: MWM experiments showed that harmine significantly improved ethanol-induced spatial learning memory deficit. Harmine exhibited anti-inflammatory effect by downregulating inflammatory factors such as IL-6, IL-1β and tumor necrosis factor-α (TNF-α) induced by ethanol. Harmine also upregulated brain-derived neurotrophic factor (BDNF) levels to exert neuroprotective effect. Moreover, harmine protected neuronal cells and increased the protein expression of myelin basic protein (MBP). The cellular results indicated that harmine protected SH-SY5Y cells from ethanol-induced cytotoxicity and upregulated the relative mRNA expression of synaptosome associated protein 25 (SNAP25), syntaxin 1A (STX1A), vesicle associated membrane protein 2 (VAMP2), synaptotagmin 1 (SYT1) and synaptophysin (SYP).

CONCLUSIONS: Harmine improved ethanol-induced memory impairment by ameliorating inflammation, increasing BDNF levels, promoting synaptic vesicle fusion, protecting myelin sheath, and modulating neurotransmitter levels. These findings provided a scientific basis for development of therapeutic drugs for alcohol-induced memory impairments and other related disorders.},
}

@article {pmid39241934,
year = {2024},
author = {Wang, XX and Ji, X and Lin, J and Wong, IN and Lo, HH and Wang, J and Qu, L and Wong, VKW and Chung, SK and Law, BYK},
title = {GPCR-Mediated Natural Products and Compounds: Potential Therapeutic Targets for the Treatment of Neurological Diseases.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {107395},
doi = {10.1016/j.phrs.2024.107395},
pmid = {39241934},
issn = {1096-1186},
abstract = {G protein-coupled receptors (GPCRs), widely expressed in the human central nervous system (CNS), perform numerous physiological functions and play a significant role in the pathogenesis of diseases. Consequently, identifying key therapeutic GPCRs targets for CNS-related diseases is garnering immense interest in research labs and pharmaceutical companies. However, using GPCRs drugs for treating neurodegenerative diseases has limitations, including side effects and uncertain effective time frame. Recognizing the rich history of herbal treatments for neurological disorders like stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), modern pharmacological research is now focusing on the understanding of the efficacy of traditional Chinese medicinal herbs and compounds in modulating GPCRs and treatment of neurodegenerative conditions. This paper will offer a comprehensive, critical review of how certain natural products and compounds target GPCRs to treat neurological diseases. Conducting an in-depth study of herbal remedies and their efficacies against CNS-related disorders through GPCRs targeting will augment our strategies for treating neurological disorders. This will not only broaden our understanding of effective therapeutic methodologies but also identify the root causes of altered GPCRs signaling in the context of pathophysiological mechanisms in neurological diseases. Moreover, it would be informative for the creation of safer and more effective GPCR-mediated drugs, thereby establishing a foundation for future treatment of various neurological diseases.},
}

@article {pmid39240975,
year = {2024},
author = {Zia-Ur-Rehman, and Awang, MK and Rashid, J and Ali, G and Hamid, M and Mahmoud, SF and Saleh, DI and Ahmad, HI},
title = {Classification of Alzheimer disease using DenseNet-201 based on deep transfer learning technique.},
journal = {PloS one},
volume = {19},
number = {9},
pages = {e0304995},
pmid = {39240975},
issn = {1932-6203},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/classification ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Aged ; Female ; Male ; Neuroimaging/methods ; Aged, 80 and over ; Brain/diagnostic imaging/pathology ; },
abstract = {Alzheimer's disease (AD) is a brain illness that causes gradual memory loss. AD has no treatment and cannot be cured, so early detection is critical. Various AD diagnosis approaches are used in this regard, but Magnetic Resonance Imaging (MRI) provides the most helpful neuroimaging tool for detecting AD. In this paper, we employ a DenseNet-201 based transfer learning technique for diagnosing different Alzheimer's stages as Non-Demented (ND), Moderate Demented (MOD), Mild Demented (MD), Very Mild Demented (VMD), and Severe Demented (SD). The suggested method for a dataset of MRI scans for Alzheimer's disease is divided into five classes. Data augmentation methods were used to expand the size of the dataset and increase DenseNet-201's accuracy. It was found that the proposed strategy provides a very high classification accuracy. This practical and reliable model delivers a success rate of 98.24%. The findings of the experiments demonstrate that the suggested deep learning approach is more accurate and performs well compared to existing techniques and state-of-the-art methods.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis/classification
Humans
*Deep Learning
*Magnetic Resonance Imaging/methods
Aged
Female
Male
Neuroimaging/methods
Aged, 80 and over
Brain/diagnostic imaging/pathology

@article {pmid39240870,
year = {2024},
author = {Shin, YB and Kim, JH and Kwon, MK and Myung, JH and Lee, DG and Jin, SG and Kang, MJ and Choi, YS},
title = {Optimized method development and validation for determining donepezil in rat plasma: A liquid-liquid extraction, LC-MS/MS, and design of experiments approach.},
journal = {PloS one},
volume = {19},
number = {9},
pages = {e0309802},
pmid = {39240870},
issn = {1932-6203},
mesh = {*Donepezil/blood/pharmacokinetics ; Animals ; *Tandem Mass Spectrometry/methods ; *Liquid-Liquid Extraction/methods ; Rats ; Chromatography, Liquid/methods ; *Piperidines/blood/pharmacokinetics/chemistry ; Cholinesterase Inhibitors/blood/pharmacokinetics ; Indans/blood/pharmacokinetics ; Male ; Reproducibility of Results ; Rats, Sprague-Dawley ; Liquid Chromatography-Mass Spectrometry ; },
abstract = {Donepezil (DPZ), a piperidine-based reversible cholinesterase inhibitor, finds extensive use in treating Alzheimer's disease (AD). Originally designed as an oral formulation, DPZ encounters drawbacks such as a brief duration of action and reduced treatment effectiveness in elderly patients with memory impairment or difficulty swallowing medications. To address these issues and improve patient compliance, researchers are actively exploring alternative DPZ formulations. Consequently, reliable methods are necessary to quantitate DPZ in biological samples for in vivo assessment. Therefore, we propose an efficient, sensitive, wide-dynamic, and cost-effective method for quantitating DPZ in rat plasma. Our method employs liquid-liquid extraction (LLE) followed by liquid chromatography and tandem mass spectrometry, enabling in vivo evaluation of novel DPZ formulations. Notably, our method requires only 20 μL of rat plasma and employs icopezil as the internal standard-a cost-effective compound with chemical similarity to DPZ. We meticulously optimized LLE conditions, taking into account factor interactions through design of experiments (DOE). Our rapid and straightforward extraction and purification involved using 500 μL of pure methyl tert-butyl ether to extract DPZ from the sample within five minutes. The dynamic range of the method extends from 0.5 ng/mL to 1,000 ng/mL, demonstrating excellent sensitivity and suitability for pharmacokinetic studies across diverse DPZ formulations. Following the FDA guidelines, we rigorously validated the developed method, evaluating selectivity, linearity (with a coefficient of determination ≥0.9999), accuracy (ranging from 96.0% to 109.6%), precision (≤13.9%), matrix effect (92.2% to 103.8%), recovery (98.5% to 106.8%), the lower limit of quantitation (0.5 ng/mL), and stability. Finally, we effectively employed the validated method for the long-term pharmacokinetic assessment of a DPZ formulation. We expect that this approach will make a substantial contribution to the advancement of new DPZ formulations, ultimately benefiting individuals afflicted by AD.},
}

*Donepezil/blood/pharmacokinetics
Animals
*Tandem Mass Spectrometry/methods
*Liquid-Liquid Extraction/methods
Rats
Chromatography, Liquid/methods
*Piperidines/blood/pharmacokinetics/chemistry
Cholinesterase Inhibitors/blood/pharmacokinetics
Indans/blood/pharmacokinetics
Male
Reproducibility of Results
Rats, Sprague-Dawley
Liquid Chromatography-Mass Spectrometry

@article {pmid39240643,
year = {2024},
author = {Cardoso, R and Teunissen, CE and Oliveira, CR},
title = {Enhancing Alzheimer's Disease Diagnosis and Care by Focusing on Plasma Biomarkers for Identifying Mild Cognitive Impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240724},
pmid = {39240643},
issn = {1875-8908},
abstract = {Biomarkers that accurately identify mild cognitive impairment (MCI) are of greater importance for Alzheimer's disease (AD) management and treatment. On the other hand, blood-based biomarkers are not only more practical but also less invasive than the common cerebrospinal fluid biomarkers. In their report in the Journal of Alzheimer's Disease, Wang and collaborators identified 67 upregulated and 220 downregulated long noncoding RNAs (lncRNAs). They further demonstrated that 4 of these lncRNAs could discriminate MCI from cognitively healthy individuals. Apart from their significance as potential biomarkers for MCI diagnosis, these lncRNAs can offer additional information on the cellular mechanisms of AD pathology.},
}

@article {pmid39240642,
year = {2024},
author = {Kostenko, A and Prezzavento, O and de Leo, G and D'Arco, D and Gulino, R and Caccamo, A and Leanza, G},
title = {Cognitive and Histopathological Alterations in Rat Models of Early- and Late-Phase Memory Dysfunction: Effects of Sigma-1 Receptor Activation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240618},
pmid = {39240642},
issn = {1875-8908},
abstract = {BACKGROUND: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction.

OBJECTIVE: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion.

METHODS: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session.

RESULTS: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation.

CONCLUSIONS: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.},
}

@article {pmid39240636,
year = {2024},
author = {Butler, T and Tey, SR and Galvin, JE and Perry, G and Bowen, RL and Atwood, CS},
title = {Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer's Disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240334},
pmid = {39240636},
issn = {1875-8908},
abstract = {The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.},
}

@article {pmid39240634,
year = {2024},
author = {Oasa, S and Chen, G and Schultzberg, M and Terenius, L},
title = {Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-231399},
pmid = {39240634},
issn = {1875-8908},
abstract = {BACKGROUND: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases maybe protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic.

OBJECTIVE: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide.

METHODS: The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed.

RESULTS: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys.

CONCLUSIONS: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously.},
}

@article {pmid39240280,
year = {2024},
author = {Miao, J and Zhang, Y and Su, C and Zheng, Q and Guo, J},
title = {Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39240280},
issn = {1559-1182},
support = {202303021222348//Shanxi Province Basic Research Program/ ; 202303021212373//Shanxi Province Basic Research Program/ ; 202303021221212//Shanxi Province Basic Research Program/ ; 2021ZD 0201801//STI2030-Major Projects/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.},
}

@article {pmid39240090,
year = {2024},
author = {Carrillo, MC and Mahinrad, S and Snyder, HM and Khachaturian, Z},
title = {The role of the Alzheimer's Association in the genesis of Alzheimer's Disease Neuroimaging Initiative.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14228},
pmid = {39240090},
issn = {1552-5279},
abstract = {Here we highlight the Alzheimer's Association's role since its inception, as a strategic collaborator with National Institutes of Health-National Institute on Aging in the development of the modern era of the Alzheimer's Movement and in making Alzheimer's disease (AD) a national priority in the United States by developing several initiatives to advance knowledge about the cause, diagnosis, and treatment of dementia. Among these collaborative undertakings, the Alzheimer's Disease Neuroimaging Initiative (ADNI) is an exemplary case, launched with groundwork by the Neuroimaging Working Group sponsored by the Association's Ronald and Nancy Reagan Research Institute on AD. The unique contribution of the Association to the development of ADNI includes participation as a member of ADNI's Private Partner Scientific Board and involvement in developing an AD biomarker standardization and validation subproject, which has led to a conceptual shift in the field to define AD based on its underlying biology. Furthermore, the creation of Worldwide ADNI (WW-ADNI) is highlighted, underscoring the global impact of these efforts. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a keystone undertaking in the evolving landscape of Alzheimer's disease (AD) research, and is now in its fourth iteration. The Alzheimer's Association has partnered with ADNI since its inception. ADNI 4 and the Association continue to collaborate, ensuring representation within the study population.},
}

@article {pmid39239152,
year = {2024},
author = {Scaduto, P and Marcatti, M and Bhatt, N and Kayed, R and Taglialatela, G},
title = {Calcineurin inhibition prevents synaptic plasticity deficit induced by brain-derived tau oligomers.},
journal = {Brain communications},
volume = {6},
number = {5},
pages = {fcae277},
pmid = {39239152},
issn = {2632-1297},
abstract = {Compelling evidence suggests that cognitive decline in Alzheimer's disease is associated with the accumulation and aggregation of tau protein, with the most toxic aggregates being in the form of oligomers. This underscores the necessity for direct isolation and analysis of brain-derived tau oligomers from patients with Alzheimer's disease, potentially offering novel perspectives into tau toxicity. Alzheimer's brain-derived tau oligomers are potent inhibitors of synaptic plasticity; however, the involved mechanism is still not fully understood. We previously reported a significantly reduced incidence of Alzheimer's disease in ageing humans chronically treated with a Food and Drug Administration-approved calcineurin inhibitor, FK506 (tacrolimus), used as an immunosuppressant after solid organ transplant. Using a combination of electrophysiological and RNA-sequencing techniques, we provide here evidence that FK506 has the potential to block the acute toxic effect of brain-derived tau oligomers on synaptic plasticity, as well as to restore the levels of some key synaptic mRNAs. These results further support FK506 as a promising novel therapeutic strategy for the treatment of Alzheimer's disease.},
}

@article {pmid39239000,
year = {2024},
author = {Uwishema, O and Kassahun Bekele, B and Nazir, A and Filbert Luta, E and Abdulnaser Al-Saab, E and Jacques Desire, I and Franklin Ozioma, C and Wojtara, M},
title = {Breaking barriers: addressing inequities in Alzheimer's disease diagnosis and treatment in Africa.},
journal = {Annals of medicine and surgery (2012)},
volume = {86},
number = {9},
pages = {5299-5303},
pmid = {39239000},
issn = {2049-0801},
abstract = {INTRODUCTION: Alzheimer's disease represents a substantial and escalating public health threat across Africa. Alzheimer's disease leads to substantial cognitive impairment and memory loss, placing a heavy burden on the affected individuals and their families, friends, and caregivers. It affects 2.67 million people in Africa, the majority of whom live in sub-Saharan Africa. The prevalence of this disease is expected to rise drastically to approximately 150 million individuals worldwide by 2050, as estimated by the WHO.

AIM: This paper offers an integrative profile of Alzheimer's disease in Africa, spanning known genetic and modifiable risks, discusses the existing challenges in diagnosis and treatment, projections on prevalence and disability-adjusted life year burden through 2050, and priority policy responses needed to rebalance the equation.

METHODS: This paper examines available literature to summarize current knowledge on risk factors, diagnosis, treatments, and burden of Alzheimer's disease in Africa. Gather epidemiological assessments, clinical guidelines, and commentary related to Alzheimer's disease in Africa.

RESULTS: The data reveals concerning realities regarding Alzheimer's disease diagnosis and care in Africa. Diagnostic infrastructure shortcomings, resource limitations, and knowledge gaps emerge as recurring barriers. Positron emission tomography scans, cerebrospinal fluid assays, and other mainstay detection modalities common in developed countries show restricted availability.

CONCLUSION: Addressing Africa's Alzheimer's disease crisis demands a multipronged strategy to uplift diagnostic capacities, treatment availability, specialist training, public awareness, and coordinated policymaking. Prioritizing biomarkers and imaging to confirm early neurodegeneration is foundational, alongside drug access expansion.},
}

@article {pmid39238424,
year = {2024},
author = {Kostic, M and Zivkovic, N and Cvetanovic, A and Basic, J and Stojanovic, I},
title = {Dissecting the immune response of CD4[+] T cells in Alzheimer's disease.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {39238424},
issn = {2191-0200},
abstract = {The formation of amyloid-β (Aβ) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aβ-specific immune response could be key factors that determine the level of Aβ-induced neuroinflammation and thus the propensity to develop AD. CD4[+] T cells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4[+] T cells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4[+] T cells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results.},
}

@article {pmid39238388,
year = {2024},
author = {de Castro, AA and Silva, HF and Garcia, MVFP and Homem-de-Mello, P and Ramalho, TC},
title = {Molecular Modeling Insights on the Pharmaceuticals and Hypotheses of Alzheimer's Disease.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673318143240823064403},
pmid = {39238388},
issn = {1875-533X},
abstract = {Alzheimer's disease (AD) stands as the predominant contributor to dementia cases. The ongoing developments in our understanding of its pathogenesis have sparked the interest of researchers, driving them to explore innovative treatment approaches. Existing therapies incorporating cholinesterase inhibitors and/or NMDA antagonists have shown limited improvement in alleviating symptoms. This, in turn, highlights the urgency for the pursuit of more effective therapeutic options. Given the annual rise in the number of individuals affected by dementia, it is imperative to allocate resources and efforts towards the exploration of novel therapeutic options. This review aims to provide a comprehensive overview of the AD-related hypotheses, along with the computational approaches employed in research within each hypothesis. In this comprehensive review, the authors shed light on using various computational tools, including diverse case studies, in the pursuit of finding efficacious treatments for AD. The development of more sophisticated diagnostic techniques is crucial, enabling early detection and intervention in the battle against this challenging condition. The potential treatments investigated in this analysis are poised to assume ever more significant functions in both preventing and treating AD, ultimately enhancing the management of the condition and the overall well-being of individuals affected by AD.},
}

@article {pmid39238068,
year = {2024},
author = {Zhu, C and Liu, J and Lin, J and Xu, J and Yu, E},
title = {Investigating the effects of Ginkgo biloba leaf extract on cognitive function in Alzheimer's disease.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {9},
pages = {e14914},
doi = {10.1111/cns.14914},
pmid = {39238068},
issn = {1755-5949},
support = {2021C03106//Key Research and Development Program of Zhejiang Province/ ; },
mesh = {*Ginkgo biloba ; *Plant Extracts/pharmacology/therapeutic use ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; *Plant Leaves/chemistry ; NF-kappa B/metabolism ; Cognition/drug effects ; Signal Transduction/drug effects ; Maze Learning/drug effects ; Mice, Inbred C57BL ; Ginkgo Extract ; },
abstract = {AIMS: Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. This study aimed to investigate the therapeutic effects of Ginkgo biloba leaf extract (GBE) on AD and explore its potential mechanisms of action.

METHODS: Key chemical components of GBE, including quercetin, luteolin, and kaempferol, were identified using network pharmacology methods. Bioinformatics analysis revealed their potential roles in AD through modulation of the PI3K/AKT/NF-κB signaling pathway.

RESULTS: Mouse experiments demonstrated that GBE improved cognitive function, enhanced neuronal morphology, and reduced serum inflammatory factors. Additionally, GBE modulated the expression of relevant proteins and mRNA.

CONCLUSION: GBE shows promise as a potential treatment for AD. Its beneficial effects on cognitive function, neuronal morphology, and inflammation may be attributed to its modulation of the PI3K/AKT/NF-κB signaling pathway. These findings provide experimental evidence for the application of Ginkgo biloba leaf in AD treatment and highlight its potential mechanisms of action.},
}

*Ginkgo biloba
*Plant Extracts/pharmacology/therapeutic use
Animals
*Alzheimer Disease/drug therapy/metabolism
Mice
Male
*Plant Leaves/chemistry
NF-kappa B/metabolism
Cognition/drug effects
Signal Transduction/drug effects
Maze Learning/drug effects
Mice, Inbred C57BL
Ginkgo Extract

@article {pmid39237792,
year = {2024},
author = {Jellinger, KA},
title = {Behavioral disorders in dementia with Lewy bodies: old and new knowledge.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {39237792},
issn = {1435-1463},
support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; },
abstract = {Dementia with Lewy bodies (DLB), the second most common primary degenerative neurocognitive disorder after Alzheimer disease, is frequently preceded by REM sleep behavior disorders (RBD) and other behavioral symptoms, like anxiety, irritability, agitation or apathy, as well as visual hallucinations and delusions, most of which occurring in 40-60% of DLB patients. Other frequent behavioral symptoms like attention deficits contribute to cognitive impairment, while attention-deficit/hyperactivity disorder (ADHD) is a risk factor for DLB. Behavioral problems in DLB are more frequent, more severe and appear earlier than in other neurodegenerative diseases and, together with other neuropsychiatric symptoms, contribute to impairment of quality of life of the patients, but their pathophysiology is poorly understood. Neuroimaging studies displayed deficits in cholinergic brainstem nuclei and decreased metabolism in frontal, superior parietal regions, cingulate gyrus and amygdala in DLB. Early RBD in autopsy-confirmed DLB is associated with lower Braak neuritic stages, whereas those without RBD has greater atrophy of hippocampus and increased tau burden. αSyn pathology in the amygdala, a central region in the fear circuitry, may contribute to the high prevalence of anxiety, while in attention dysfunctions the default mode and dorsal attention networks displayed diverging activity. These changes suggest that behavioral disorders in DLB are associated with marked impairment in large-scale brain structures and functional connectivity network disruptions. However, many pathobiological mechanisms involved in the development of behavioral disorders in DLB await further elucidation in order to allow an early diagnosis and adequate treatment to prevent progression of these debilitating disorders.},
}

@article {pmid39237748,
year = {2024},
author = {Shekho, D and Mishra, R and Kamal, R and Bhatia, R and Awasthi, A},
title = {Breaking Barriers in Alzheimer's Disease: the Role of Advanced Drug Delivery Systems.},
journal = {AAPS PharmSciTech},
volume = {25},
number = {7},
pages = {207},
pmid = {39237748},
issn = {1530-9932},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; Animals ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Drug Delivery Systems/methods
Animals
Biomarkers/metabolism
Amyloid beta-Peptides/metabolism
Brain/metabolism/drug effects
tau Proteins/metabolism

@article {pmid39237715,
year = {2024},
author = {Kang, C},
title = {Donanemab: First Approval.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {39237715},
issn = {1179-1950},
abstract = {Donanemab (donanemab-azbt; Kisunla[TM]) is an amyloid β-directed antibody developed by Eli Lilly and Company for the treatment of Alzheimer's disease. Donanemab recently received approval in the USA for the treatment of adults with early symptomatic Alzheimer's disease (patients with mild cognitive impairment or mild dementia stage of disease). This article summarizes the milestones in the development of donanemab leading to this first approval for Alzheimer's disease.},
}

@article {pmid39237082,
year = {2024},
author = {Wu, K and Zhang, X and Zheng, M and Zhang, J and Chen, W},
title = {A Causal Mediation Approach to Account for Interaction of Treatment and Intercurrent Events: Using Hypothetical Strategy.},
journal = {Statistics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/sim.10212},
pmid = {39237082},
issn = {1097-0258},
support = {2022B1515020094//Natural Science Foundation of Guangdong Province/ ; 72074229//National Natural Science Foundation of China/ ; },
abstract = {Hypothetical strategy is a common strategy for handling intercurrent events (IEs). No current guideline or study considers treatment-IE interaction to target the estimand in any one IE-handling strategy. Based on the hypothetical strategy, we aimed to (1) assess the performance of three estimators with different considerations for the treatment-IE interaction in a simulation and (2) compare the estimation of these estimators in a real trial. Simulation data were generalized based on realistic clinical trials of Alzheimer's disease. The estimand of interest was the effect of treatment with no IE occurring under the hypothetical strategy. Three estimators, namely, G-estimation with and without interaction and IE-ignored estimation, were compared in scenarios where the treatment-IE interaction effect was set as -50% to 50% of the main effect. Bias was the key performance measure. The real case was derived from a randomized trial of methadone maintenance treatment. Only G-estimation with interaction exhibited unbiased estimations regardless of the existence, direction or magnitude of the treatment-IE interaction in those scenarios. Neglecting the interaction and ignoring the IE would introduce a bias as large as 0.093 and 0.241 (true value, -1.561) if the interaction effect existed. In the real case, compared with G-estimation with interaction, G-estimation without interaction and IE-ignored estimation increased the estimand of interest by 33.55% and 34.36%, respectively. This study highlights the importance of considering treatment-IE interaction in the estimand framework. In practice, it would be better to include the interaction in the estimator by default.},
}

@article {pmid39236857,
year = {2024},
author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P},
title = {Dysfunctional Mitochondria in Age-related Neurodegeneration: Utility of Melatonin as an Antioxidant Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102480},
doi = {10.1016/j.arr.2024.102480},
pmid = {39236857},
issn = {1872-9649},
abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.},
}

@article {pmid39235760,
year = {2024},
author = {Palai, AK and Kumar, A and Mazahir, F and Sharma, A and Yadav, AK},
title = {Synthesis and characterization of fullerene-based nanocarrier for targeted delivery of quercetin to the brain.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/20415990.2024.2365620},
pmid = {39235760},
issn = {2041-6008},
abstract = {Aim: Preparation of quercetin fullerene conjugate (QFC) for nose-to-brain delivery and their in vitro and ex vivo characterizations.Methods: Carboxylated fullerene was converted into acetylated fullerene and quercetin was conjugated and physically adsorbed on acetylated fullerene.Results: The particle size and zeta potential of QFC and chitosan-coated QFC (CC-QFC) were found to be 179.2 ± 1.10, 293.4 ± 2.757, -5.28 ± 1.43 and 11.6 ± 0.4 respectively. The entrapment efficiency, loading efficiency of QFC were found to be 85.55% and 42.77%. The MTT assay revealed 80.69% SH-SY5Y cell viability at a concentration of 50 μg/ml. CC-QFC showed remarkable (89.20%) ex vivo mucoadhesive properties compared with QFC (66.67%). Further study showed no significant ciliotoxicity by CC-QFC.Conclusion: The obtained results suggested the potential of CC-QFC for treatment in Alzheimer's disease.},
}

@article {pmid39235700,
year = {2024},
author = {Mu, B and Jing, J and Li, R and Li, C},
title = {METTL14 inhibits Aβ1-42-induced neuronal injury through regulating the stability of CBLN4 mRNA in Alzheimer's disease.},
journal = {Journal of bioenergetics and biomembranes},
volume = {},
number = {},
pages = {},
pmid = {39235700},
issn = {1573-6881},
abstract = {Previous studies have suggested that N6-methyladenosine (mA) modification of RNA affects fundamental aspects of RNA metabolism, and mA dysregulation is implicated in various human diseases, including Alzheimer's disease (AD). This study is designed to explore the role and mechanism of methyltransferase-like 14 (METTL14) in the pathogenesis of AD. SK-N-SH cells were treated with Aβ1-42 to establish an in vitro model of AD. Cerebellin 4 (CBLN4) and METTL14 expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability and apoptosis were analyzed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry assay. B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase-3, total-caspase-3, C/EBP homologous protein (CHOP), and glucose-related protein 78 (GRP78) protein levels were determined using Western blot. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) products were examined using special assay kits. Interaction between CBLN4 and METTL14 was verified using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays. CBLN4 and METTL14 expression was decreased in Aβ1-42-treated SK-N-SH cells. Upregulation of CBLN4 relieved Aβ1-42-induced SK-N-SH cell apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in vitro. At the molecular level, METTL14 could improve the stability and expression of CBLN4 mRNA via m6A methylation. Our findings indicated that m6A methylase METTL14-mediated upregulation of CBLN4 mRNA stability could repress Aβ1-42-triggered SK-N-SH cell injury, providing a promising therapeutic target for AD treatment.},
}

@article {pmid39235155,
year = {2024},
author = {Lemos, R and Pérez-Badell, Y and De Nisco, M and Carpentieri, A and Suárez, M and Pedatella, S},
title = {Organic Chimeras Based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β-amyloid Peptide Aggregation.},
journal = {ChemPlusChem},
volume = {},
number = {},
pages = {e202400404},
doi = {10.1002/cplu.202400404},
pmid = {39235155},
issn = {2192-6506},
abstract = {The aggregation of β-amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel-Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP-D3(BJ)/6-311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ-peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells.},
}

@article {pmid39234102,
year = {2024},
author = {Liu, B and Cui, D and Liu, J and Shi, JS},
title = {Transcriptome analysis of the aged SAMP8 mouse model of Alzheimer's disease reveals novel molecular targets of formononetin protection.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1440515},
pmid = {39234102},
issn = {1663-9812},
abstract = {BACKGROUND: Senescence-accelerated mouse prone 8 (SAMP8) and age-matched SAMR1 mice are used to study the pathogenesis and therapeutics of Alzheimer's disease (AD); however, the molecular mechanisms are not completely understood.

OBJECTIVE: This study aimed to examine the effects of the 5-month administration of formononetin in SAMP8 mice and used RNA-seq to explore the molecular targets.

METHODS: SAMP8 mice were orally administered formononetin (0, 8, and 16 mg/kg) from 4 months of age, and age-matched SAMR1 mice were used as controls. Behavioral tests were performed in 9-month-old mice, followed by histopathologic analysis. Total RNA from the hippocampus was isolated and subjected to RNA-seq, RT-qPCR, and bioinformatics analysis.

RESULTS: The 9-month-old SAMP8 mice exhibited cognition deficits, evidenced by novel object recognition, open-field test, elevated plus maze, and passive avoidance. Nissl bodies in the cortex and hippocampus were decreased. Formononetin treatments ameliorated behavioral deficits and improved morphological changes, which were evidenced by Nissl and H&E staining. RNA-seq revealed distinct gene expression patterns between SAMP8 and SAMR1 mice. Differentially expressed genes in SAMP8 mice were attenuated or normalized by formononetin. Ingenuity pathway analysis (IPA) of canonical pathway and upstream regulators revealed increases in proinflammatory factors and immune dysfunction and decreases in NRF2 and SIRT-1 signaling pathways, leading to neuroinflammation. Formononetin treatment attenuated or reversed these molecular changes. The transcriptome of SAMP8 mice was correlated with transcriptomic profiles of other AD mouse models in the GEO database.

CONCLUSION: Neuroinflammation and decreased antioxidant and SIRT-1 signaling contributed to cognitive deficits in aged SAMP8 mice, which are potential therapeutic targets of formononetin in combination with other therapies.},
}

@article {pmid39233848,
year = {2024},
author = {Cheng, M and Yuan, C and Ju, Y and Liu, Y and Shi, B and Yang, Y and Jin, S and He, X and Zhang, L and Min, D},
title = {Quercetin Attenuates Oxidative Stress and Apoptosis in Brain Tissue of APP/PS1 Double Transgenic AD Mice by Regulating Keap1/Nrf2/HO-1 Pathway to Improve Cognitive Impairment.},
journal = {Behavioural neurology},
volume = {2024},
number = {},
pages = {5698119},
pmid = {39233848},
issn = {1875-8584},
mesh = {Animals ; *Quercetin/pharmacology ; *Mice, Transgenic ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; *Alzheimer Disease/metabolism/drug therapy/genetics ; *NF-E2-Related Factor 2/metabolism/drug effects/genetics ; *Oxidative Stress/drug effects ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; *Heme Oxygenase-1/metabolism ; *Apoptosis/drug effects ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Disease Models, Animal ; *Brain/drug effects/metabolism/pathology ; Signal Transduction/drug effects ; Presenilin-1/genetics/metabolism ; Male ; Mice, Inbred C57BL ; Membrane Proteins/metabolism/genetics ; Antioxidants/pharmacology/metabolism ; },
abstract = {Objective: The objective of the study is to investigate whether quercetin ameliorates Alzheimer's disease (AD)-like pathology in APP/PS1 double transgenic mice and its hypothesized mechanism, contributing to the comprehension of AD pathogenesis. Methods: A total of 30 APP/PS1 transgenic mice were randomized into model group (APP/PS1), quercetin group (APP/PS1+Q), and donepezil hydrochloride group (APP/PS1+DON). Simultaneously, there were 10 C57 mice of the same age served as a control group. Three months posttreatment, the effects of quercetin on AD mice were evaluated using the Morris water maze (MWM) test, Y maze experiment, immunohistochemistry, immunofluorescence, and western blotting. Results: Results from the water maze and Y maze indicated that quercetin significantly improved cognitive impairment in APP/PS1 transgenic AD mice. Additionally, serum enzyme-linked immunosorbent assay (ELISA) results demonstrated that quercetin elevated MDA, superoxide dismutase (SOD), CAT, GSH, acetylcholine (ACh), and acetylcholinesterase (AChE) levels in AD mice. Hematoxylin-eosin (HE) staining, Nissl staining, and hippocampal tissue thioflavine staining revealed that quercetin reduced neuronal damage and Aβ protein accumulation in AD mice. Western blot validated protein expression in the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway associated with oxidative stress and apoptosis, confirming quercetin's potential molecular mechanism of enhancing AD mouse cognition. Furthermore, western blot findings indicate that quercetin significantly alters protein expression in the Keap1/Nrf2/HO-1 pathway. Moreover, molecular docking analysis suggests that Keap1, NQO1, HO-1, caspase-3, Bcl-2, and Bax proteins in the Keap1/Nrf2/HO-1 pathway may be potential regulatory targets of quercetin. These findings will provide a molecular basis for quercetin's clinical application in AD treatment. Conclusion: Quercetin can improve cognitive impairment and AD-like pathology in APP/PS1 double transgenic mice, potentially related to quercetin's activation of the Keap1/Nrf2/HO-1 pathway and reduction of cell apoptosis.},
}

Animals
*Quercetin/pharmacology
*Mice, Transgenic
*Kelch-Like ECH-Associated Protein 1/metabolism/genetics
*Alzheimer Disease/metabolism/drug therapy/genetics
*NF-E2-Related Factor 2/metabolism/drug effects/genetics
*Oxidative Stress/drug effects
Mice
*Cognitive Dysfunction/drug therapy/metabolism
*Heme Oxygenase-1/metabolism
*Apoptosis/drug effects
*Amyloid beta-Protein Precursor/genetics/metabolism
*Disease Models, Animal
*Brain/drug effects/metabolism/pathology
Signal Transduction/drug effects
Presenilin-1/genetics/metabolism
Male
Mice, Inbred C57BL
Membrane Proteins/metabolism/genetics
Antioxidants/pharmacology/metabolism

@article {pmid39233699,
year = {2024},
author = {},
title = {68th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts: September 12-14, 2024, Regensburg, Germany.},
journal = {Free neuropathology},
volume = {5},
number = {},
pages = {},
doi = {10.17879/freeneuropathology-2024-5842},
pmid = {39233699},
issn = {2699-4445},
abstract = {Dear colleagues, It is my pleasure and honor to host the 68[th] Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) in Regensburg. Since the Magdeburg meeting in 2019 this is the first pure national meeting of our society that will be held in presence after five long years. While the meeting in 2020 was cancelled due to the Corona pandemic, the 2021 meeting (organized by the colleagues in Gießen) took place as a mere online meeting. In 2022 and 2023 our national society meetings were embedded in the "Neurowoche" and the International Congress of Neuropathology in Berlin. We are enthusiastic about this years' reunion of our society in Regensburg. In our Regensburg meeting, we aim to provide a comprehensive update on the major and hot topics in neuropathology. Neuropathologists address some of the currently most relevant and discussed health care issues, such as for example cancer, neuroimmunological diseases like Multiple Sclerosis, neurodegenerative diseases including Alzheimer's and Parkinson's, and muscle/nerve diseases. As tissue specialists, neuropathologists directly study diseases in human materials. Neuropathologists use state of-the-art methods to uncover disease processes on the molecular level. During our congress, we will hear a lot on the methodical progress made in this regard. Neuropathology is also becoming increasingly clinical as many of our scientific and diagnostic findings influence and directly guide treatment decisions. We were able to attract renowned national and international speakers and our meeting will allow for an intensive interchange both within our society and with our neighboring disciplines. Program highlights include a Pre-Congress hands-on Workshop on Next Generation Sequencing, a session on Molecular Tumorboards and a Mini-Symposium on Quality Assurance in Neuropathology. We are delighted about the submission of 31 abstracts covering the research fields Neurooncology, Neuroimmunology, Muscle/Nerve, Neurodegeneration, and Methods/Free Topics. The abstracts are published below in this edition of Free Neuropathology. I want to thank the scientific committee of our congress for helping in evaluating the submissions and selecting the poster talks and poster spotlight presentations. Many of the abstracts were submitted by our young researchers. They deserve our special attention! Posters will be exhibited throughout the entire congress and we will have plenty of time for poster viewing and discussions on Thursday evening at the Welcome Reception and at the main poster session on Friday at noon. So let me again welcome you all to our beautiful city of Regensburg. I am looking forward to inspiring talks, vivid discussions and enriching encounters with like-minded people. Yours, Prof. Dr. Markus J. Riemenschneider Regensburg University Hospital, Department of Neuropathology Congress President DGNN Annual Meeting 2024.},
}

@article {pmid39233146,
year = {2024},
author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q},
title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102472},
doi = {10.1016/j.arr.2024.102472},
pmid = {39233146},
issn = {1872-9649},
abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.},
}

@article {pmid39232876,
year = {2024},
author = {Sánchez-Fernández, N and Gómez-Acero, L and Castañé, A and Adell, A and Campa, L and Bonaventura, J and Brito, V and Ginés, S and Queiróz, F and Silva, H and Lopes, JP and Lopes, CR and Radošević, M and Gasull, X and Cunha, RA and Köfalvi, A and Ferreira, SG and Ciruela, F and Aso, E},
title = {A combination of Δ[9]-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00439},
doi = {10.1016/j.neurot.2024.e00439},
pmid = {39232876},
issn = {1878-7479},
abstract = {A combination of Δ[9]-tetrahydrocannabinol (Δ[9]-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ[9]-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ[9]-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.},
}

@article {pmid39232405,
year = {2024},
author = {Luo, M and He, Z and Cui, H and Ward, P and Chen, YP and , },
title = {Dual attention based fusion network for MCI Conversion Prediction.},
journal = {Computers in biology and medicine},
volume = {182},
number = {},
pages = {109039},
doi = {10.1016/j.compbiomed.2024.109039},
pmid = {39232405},
issn = {1879-0534},
abstract = {Alzheimer's disease (AD) severely impacts the lives of many patients and their families. Predicting the progression of the disease from the early stage of mild cognitive impairment (MCI) is of substantial value for treatment, medical research and clinical trials. In this paper, we propose a novel dual attention network to classify progressive MCI (pMCI) and stable MCI (sMCI) using both magnetic resonance imaging (MRI) and neurocognitive metadata. A 3D CNN ShuffleNet V2 model is used as the network backbone to extract MRI image features. Then, neurocognitive metadata is used to guide the spatial attention mechanism to steer the model to focus attention on the most discriminative regions of the brain. In contrast to traditional fusion methods, we propose a ViT based self attention fusion mechanism to fuse the neurocognitive metadata with the 3D CNN feature maps. The experimental results show that our proposed model achieves an accuracy, AUC, and sensitivity of 81.34%, 0.874, and 0.85 respectively using 5-fold cross validation evaluation. A comprehensive experimental study shows our proposed approach significantly outperforms all previous methods for MCI progression classification. In addition, an ablation study shows both fusion methods contribute to the high final performance.},
}

@article {pmid39232030,
year = {2024},
author = {León-Espinosa, G and Murillo, AMM and Turegano-Lopez, M and DeFelipe, J and Holgado, M},
title = {Phosphorylated Tau at T181 accumulates in the serum of hibernating Syrian hamsters and rapidly disappears after arousal.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {20562},
pmid = {39232030},
issn = {2045-2322},
support = {FUSP-PPC-19-264E8B2F//Universidad San Pablo - CEU/ ; PID2021-127924NB-I00//MCIN/AEI/10.13039/501100011033; CSIC Interdisciplinary Thematic Platform - Cajal Blue Brain (PTI-BLUEBRAIN; Spain)/ ; CB06/05/0066//CIBERNED, ISCIII/ ; SOL-00116599//Center for the Development of Industrial Technology (CDTI)/ ; IND2019/IND-17207//Spanish Ministry of Economy and Competitiveness project TEC2017-84846-R, Madrid Regional/ ; },
mesh = {Animals ; *tau Proteins/metabolism/blood ; *Hibernation ; *Mesocricetus ; Phosphorylation ; Cricetinae ; Biomarkers/blood ; Arousal/physiology ; Alzheimer Disease/metabolism/blood ; Male ; Brain/metabolism ; },
abstract = {The search for biomarkers for the early diagnosis of neurodegenerative diseases is a growing area. Numerous investigations are exploring minimally invasive and cost-effective biomarkers, with the detection of phosphorylated Tau (pTau) protein emerging as one of the most promising fields. pTau is the main component of the paired helical filaments found in the brains of Alzheimer's disease cases and serves as a precursor in the formation of neurofibrillary tangles (NFTs). Recent research has revealed that analysis of p-Tau181, p-Tau217 and p-Tau231 in blood may be an option for detecting the preclinical stage of Alzheimer's disease. In this study, we have analyzed the values of pTau 181 in the serum of Syrian hamsters during hibernation. Naturally, over the course of hibernation, these animals exhibit a reversible accumulation of pTau in the brain tissue, which rapidly disappears upon awakening. A biosensing system based on the interferometric optical detection method was used to measure the concentration of pTau181 protein in serum samples from Syrian hamsters. This method eliminates the matrix effect and amplifies the signal obtained by using silicon dioxide nanoparticles (SiO2 NPs) biofunctionalized with the αpTau181 antibody. Our results indicate a substantial increase in the serum concentration of pTau in threonine-181 during hibernation, which disappears completely 2-3 h after awakening. Investigating the mechanism by which pTau protein appears in the blood non-pathologically may enhance current diagnostic techniques. Furthermore, since this process is reversible, and no tangles are detected in the brains of hibernating hamsters, additional analysis may contribute to the discovery of improved biomarkers. Additionally, exploring drugs targeting pTau to prevent the formation of tangles or studying the outcomes of any pTau-targeted treatment could be valuable.},
}

Animals
*tau Proteins/metabolism/blood
*Hibernation
*Mesocricetus
Phosphorylation
Cricetinae
Biomarkers/blood
Arousal/physiology
Alzheimer Disease/metabolism/blood
Male
Brain/metabolism

@article {pmid39231845,
year = {2024},
author = {Lee, D and Shen, AM and Garbuzenko, OB and Minko, T},
title = {Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.},
journal = {The AAPS journal},
volume = {26},
number = {5},
pages = {99},
pmid = {39231845},
issn = {1550-7416},
mesh = {*Liposomes ; *Alzheimer Disease/drug therapy ; Humans ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors ; *Aspartic Acid Endopeptidases/antagonists & inhibitors ; *RNA, Small Interfering/administration & dosage ; *Administration, Intranasal ; *Donepezil/administration & dosage ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Brain/metabolism/drug effects ; Piperidines/administration & dosage/pharmacokinetics/pharmacology ; Nasal Mucosa/metabolism/drug effects ; Indans/administration & dosage/pharmacokinetics ; Amyloid beta-Peptides/metabolism ; },
abstract = {β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.},
}

*Liposomes
*Alzheimer Disease/drug therapy
Humans
*Amyloid Precursor Protein Secretases/antagonists & inhibitors
*Aspartic Acid Endopeptidases/antagonists & inhibitors
*RNA, Small Interfering/administration & dosage
*Administration, Intranasal
*Donepezil/administration & dosage
Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism/drug effects
Brain/metabolism/drug effects
Piperidines/administration & dosage/pharmacokinetics/pharmacology
Nasal Mucosa/metabolism/drug effects
Indans/administration & dosage/pharmacokinetics
Amyloid beta-Peptides/metabolism

@article {pmid39230033,
year = {2024},
author = {Chen, YY and Chang, CJ and Liang, YW and Tseng, HY and Li, SJ and Chang, CW and Wu, YT and Shao, HH and Chen, PC and Lai, ML and Deng, WC and Hsu, R and Lo, YC},
title = {Utilizing diffusion tensor imaging as an image biomarker in exploring the therapeutic efficacy of forniceal deep brain stimulation in a mice model of Alzheimer's disease.},
journal = {Journal of neural engineering},
volume = {21},
number = {5},
pages = {},
doi = {10.1088/1741-2552/ad7322},
pmid = {39230033},
issn = {1741-2552},
mesh = {Animals ; *Alzheimer Disease/therapy/diagnostic imaging/psychology ; *Deep Brain Stimulation/methods ; Mice ; *Diffusion Tensor Imaging/methods ; *Mice, Transgenic ; *Disease Models, Animal ; *Fornix, Brain/diagnostic imaging ; Biomarkers ; Male ; Treatment Outcome ; },
abstract = {Objective.With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established.Approach.This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS.Main results.The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS.Significance.The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior.},
}

Animals
*Alzheimer Disease/therapy/diagnostic imaging/psychology
*Deep Brain Stimulation/methods
Mice
*Diffusion Tensor Imaging/methods
*Mice, Transgenic
*Disease Models, Animal
*Fornix, Brain/diagnostic imaging
Biomarkers
Male
Treatment Outcome

@article {pmid39229896,
year = {2024},
author = {de Havenon, A and Gottesman, RF and Willamson, JD and Rost, N and Sharma, R and Li, V and Littig, L and Stulberg, E and Falcone, GJ and Prabhakaran, S and Schneider, ALC and Sheth, KN and Pajewski, NM and Brickman, AM},
title = {White matter hyperintensity on MRI and plasma Aβ42/40 ratio additively increase the risk of cognitive impairment in hypertensive adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14126},
pmid = {39229896},
issn = {1552-5279},
support = {K23NS105924//NIH/NINDS/ ; UG3NS130228//NIH/NINDS/ ; R01NS130189//NIH/NINDS/ ; U01NS106513//NIH/NINDS/ ; R01NS110721//NIH/NINDS/ ; R01NR018335//NIH/NINDS/ ; R01EB301114//NIH/NINDS/ ; R01MD016178//NIH/NINDS/ ; U24NS107215//NIH/NINDS/ ; U24NS107136//NIH/NINDS/ ; U24NS129500//NIH/NINDS/ ; K23NS123340//American Heart Association/ ; W81XWH-21-1-0590//Department of Defense/ ; HT9425-23-1-0981//Department of Defense/ ; K23NS121634//Department of Defense/ ; 1R38HL167282-01//Utah Stimulating Access to Research in Residency/ ; R01AG055606/AG/NIA NIH HHS/United States ; R01AG065805/AG/NIA NIH HHS/United States ; U24AG082930/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study.

METHODS: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aβ)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aβ risk, (3) WMH risk, and (4) combined high risk.

RESULTS: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category.

DISCUSSION: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology.

HIGHLIGHTS: White matter hyperintensity (WMH) and plasma amyloid (Aβ42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aβ42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research.},
}

@article {pmid39229584,
year = {2024},
author = {Shahidi, S and Soleimani Asl, S and Gholamigeravand, B and Afshar, S and Hashemi-Firouzi, N and Samzadeh-Kermani, A and Majidi, M and Amiri, K},
title = {Effect of mesenchymal stem cells and polyvinyl alcohol-coated selenium nanoparticles on rats with Alzheimer-like phenotypes.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {10},
pages = {1268-1275},
pmid = {39229584},
issn = {2008-3866},
abstract = {OBJECTIVES: Mesenchymal stem cell (MSC) transplantation represents a promising approach for treating Alzheimer's disease (AD). These stem cells, however, have a short lifespan following transplantation into recipient animals. Selenium nanoparticles, due to their size, aid in drug delivery for brain disorders. This study investigated the therapeutic effect of MSCs and polyvinyl alcohol (PVA)-coated selenium nanoparticles (SeNPs) in a rat model of AD.

MATERIALS AND METHODS: An Alzheimer-like phenotype was induced through intracerebroventricular (ICV) administration of streptozotocin (STZ). Rats were assigned to five groups: control, Alz (STZ; 3 mg/kg, 10 μl, ICV), Alz+stem cell (ICV transplantation), Alz+SeNP (0.4 mg/kg, orally), and Alz+stem cell+SeNPs. The ICV administration of STZ mimicked some aspects of AD in the Alz groups. SeNPs were administrated for 30 days following STZ administration. The novel object recognition (NOR) and passive avoidance learning (PAL) tests were used to evaluate cognition and memory. Oxidative stress biomarkers and brain-derived neurotrophic factor (BDNF) were assessed by biochemical analysis, ELISA kits, and Congo red staining, respectively.

RESULTS: The combined therapy of PVA-coated SeNPs and MSC transplantation was more effective in enhancing memory reacquisition compared to either SeNPs or MSCs alone. The use of stem cells in conjunction with PVA-coated SeNPs significantly boosted anti-oxidant capacity.

CONCLUSION: The results suggest that the joint treatment with PVA-coated SeNPs and MSCs offers considerable neuroprotection against AD in animal models.},
}

@article {pmid39229480,
year = {2024},
author = {Shane, R and Kremen, S and Tan, ZS and Tran, H and Tu, TG and Sicotte, NL},
title = {Lecanemab Planning: Blueprint for Safe and Effective Management of Complex Therapies.},
journal = {Neurology. Clinical practice},
volume = {14},
number = {6},
pages = {e200361},
pmid = {39229480},
issn = {2163-0402},
abstract = {BACKGROUND: Approximately 6.9 million American individuals have Alzheimer dementia and 50% have mild disease. Lecanemab, an approved antiamyloid antibody, is associated with modest reduction in functional decline in patients with mild dementia or mild cognitive impairment. In Clarity-AD, 239 (26.6%) of patients experienced amyloid-related imaging abnormalities (ARIAs) overall (i.e., ARIAs associated with hemorrhages or edema). The complexity of treatment and risks of adverse events necessitate a multidisciplinary collaborative approach.

RECENT FINDINGS: With limited treatment options, lecanemab approval generated significant interest among clinicians, patients, and families. Lecanemab treatment requires biweekly infusions along with ongoing imaging tests, laboratory monitoring, patient assessment, drug interaction screening, and cognitive function monitoring. Processes to support patient selection, access, and safety are important given the monitoring requirements and total cost of care.

IMPLICATIONS FOR PRACTICE: The planning process for lecanemab can serve as a blueprint to support safe and effective management of therapeutic innovation in neurology and other areas.},
}

@article {pmid39229221,
year = {2024},
author = {Chen, W and Liu, X and Munoz, VR and Kahn, CR},
title = {Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aβ and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.22.609112},
pmid = {39229221},
issn = {2692-8205},
abstract = {Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimers disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprograming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ; plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to take up Aβ; such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.},
}

@article {pmid39229198,
year = {2024},
author = {Gutiérrez-Jiménez, E and Rasmussen, PM and Mikkelsen, IK and Kura, S and Fruekilde, SK and Hansen, B and Bordoni, L and Carlsen, J and Palmfeldt, J and Boas, DA and Sakadžic, S and Vinogradov, SA and El Khatib, M and Ramos-Cejudo, J and Wied, B and Leduc-Galindo, D and Canepa, E and Mar, AC and Gamallo-Lana, B and Fossati, S and Østergaard, L},
title = {Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.22.609091},
pmid = {39229198},
issn = {2692-8205},
abstract = {To enhance early diagnosis and treatment of Alzheimer·s disease (AD), understanding the pathological changes before symptoms arise is crucial. The continuum model of AD suggest that Aβ beta (Aβ) accumulation precedes symptoms by at least 15 years, with vascular changes detectable around this time. Disturbances in capillary flow dynamics have been linked to reduced oxygen delivery to brain tissue, but evidence in presymptomatic AD remains elusive. We examined capillary flow dynamics in presymptomatic Tg-SwDI mice and the capacity of carbonic anhydrase inhibitors (CAIs) to prevent capillary flow disturbances. Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Aβ load in cognitively normal 9-10-month-old Tg-SwDI mice. Treated mice showed ameliorated capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. These findings underscore the importance of capillary flow disturbances in presymptomatic AD and highlight CAIs· potential for preserving vascular integrity in early AD.},
}

@article {pmid39226707,
year = {2024},
author = {Bian, ZY and Li, PX and Feng, XY and Zhou, YR and Cheng, FY and Dong, WX and Xiang, P and Tang, JJ},
title = {Design, synthesis, and biological evaluation of imidazolylacetophenone oxime derivatives as novel brain-penetrant agents for Alzheimer's disease treatment.},
journal = {European journal of medicinal chemistry},
volume = {278},
number = {},
pages = {116794},
doi = {10.1016/j.ejmech.2024.116794},
pmid = {39226707},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 μM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aβ42 aggregation. Moreover, the selected nuclide [[18]F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.},
}

@article {pmid39226167,
year = {2024},
author = {Li, C and Zhao, Q and Feng, L and Li, M},
title = {Emerging Roles of Adaptive Immune Response in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0564},
pmid = {39226167},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by progressive cognitive decline. Pathologically, this disease is associated with the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFTs), and neuroinflammation. Current drug treatments primarily focus on managing symptoms rather than stopping disease progression. Disease-modifying therapies target the clearance of amyloid plaques through active and passive immunity methods. Although successful in animal models, human trials have shown adverse effects, such as meningoencephalitis, in a small number of patients who received active immunity methods. The efficacy of active immunity methods in treating AD remains uncertain, but passive immunity methods amyloid-beta (Abeta)-specific monoclonal antibody therapies such as aducanumab and lecanemab have been approved by the FDA. Despite the limitations of immune-based therapies, T-cell, and chimeric antigen receptor-based treatments show promise, but new guidelines are necessary to address potential adverse events. Research into the relationship between adaptive immune responses and AD is expected to provide innovative treatment approaches.},
}

@article {pmid39226164,
year = {2024},
author = {Cai, J and Ni, YQ and Liu, YS},
title = {Exploring the Frontier: Antisense Long Non-Coding RNAs as Key Regulators in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0762},
pmid = {39226164},
issn = {2152-5250},
abstract = {Alzheimer's Disease (AD) is the most prevalent, costly, and fatal neurodegenerative disorder of this century. Two hallmark features of AD are the anomalous cleavage of amyloid precursor protein (APP), which leads to the accumulation of amyloid-beta (Aβ), and the hyperphosphorylation of tau protein. Despite extensive research efforts, the pathology and pathogenesis of AD remain elusive. Recent investigations have highlighted the close association between antisense long non-coding RNAs (AS-lncRNAs) and various biological and functional aspects of AD. However, many AS-lncRNAs implicated in AD have not yet been comprehensively compiled and discussed. This paper reviews the role of AS-lncRNAs in neurodegenerative diseases, outlines their association with AD, and offers novel insights into the potential applications of antisense RNAs in the diagnosis and treatment of AD.},
}

@article {pmid39225243,
year = {2024},
author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y},
title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.8322},
pmid = {39225243},
issn = {1099-1573},
support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; },
abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.},
}

@article {pmid39225173,
year = {2024},
author = {Kuşi, M and Becer, E and Vatansever, HS},
title = {Basic approach on the protective effects of hesperidin and naringin in Alzheimer's disease.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/1028415X.2024.2397136},
pmid = {39225173},
issn = {1476-8305},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. This situation imposes a great burden on individuals, both economically and socially. Today, an effective method for treating the disease and protective approach to tau accumulation has not been developed yet. Studies have been conducted on the effects of hesperidin and naringin flavonoids found in citrus fruits on many diseases.

METHODS: In this review, the pathophysiology of AD is defined, and the effects of hesperidin and naringin on these factors are summarized.

RESULTS: Studies have shown that both components may potentially affect AD due to their antioxidative and anti-inflammatory properties. Based on these effects of the components, it has been shown that they may have ameliorative effects on Aβ, α-synuclein aggregation, tau pathology, and cognitive functions in the pathophysiology of AD.

DISCUSSION: There are studies suggesting that hesperidin and naringin may be effective in the prevention/treatment of AD. When these studies are examined, it is seen that more studies should be conducted on the subject.},
}

@article {pmid39224475,
year = {2024},
author = {Kang, DW and Wang, SM and Um, YH and Kim, S and Kim, T and Kim, D and Lee, CU and Lim, HK},
title = {Transcranial direct current stimulation and neuronal functional connectivity in MCI: role of individual factors associated to AD.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1428535},
pmid = {39224475},
issn = {1664-0640},
abstract = {BACKGROUND: Alzheimer's disease (AD) encompasses a spectrum that may progress from mild cognitive impairment (MCI) to full dementia, characterized by amyloid-beta and tau accumulation. Transcranial direct current stimulation (tDCS) is being investigated as a therapeutic option, but its efficacy in relation to individual genetic and biological risk factors remains underexplored.

OBJECTIVE: To evaluate the effects of a two-week anodal tDCS regimen on the left dorsolateral prefrontal cortex, focusing on functional connectivity changes in neural networks in MCI patients resulting from various possible underlying disorders, considering individual factors associated to AD such as amyloid-beta deposition, APOE ϵ4 allele, BDNF Val66Met polymorphism, and sex.

METHODS: In a single-arm prospective study, 63 patients with MCI, including both amyloid-PET positive and negative cases, received 10 sessions of tDCS. We assessed intra- and inter-network functional connectivity (FC) using fMRI and analyzed interactions between tDCS effects and individual factors associated to AD.

RESULTS: tDCS significantly enhanced intra-network FC within the Salience Network (SN) and inter-network FC between the Central Executive Network and SN, predominantly in APOE ϵ4 carriers. We also observed significant sex*tDCS interactions that benefited inter-network FC among females. Furthermore, the effects of multiple modifiers, particularly the interaction of the BDNF Val66Met polymorphism and sex, were evident, as demonstrated by increased intra-network FC of the SN in female Met non-carriers. Lastly, the effects of tDCS on FC did not differ between the group of 26 MCI patients with cerebral amyloid-beta deposition detected by flutemetamol PET and the group of 37 MCI patients without cerebral amyloid-beta deposition.

CONCLUSIONS: The study highlights the importance of precision medicine in tDCS applications for MCI, suggesting that individual genetic and biological profiles significantly influence therapeutic outcomes. Tailoring interventions based on these profiles may optimize treatment efficacy in early stages of AD.},
}

@article {pmid39224128,
year = {2024},
author = {Olalekan, SO and Obakachi, VA and Badeji, AA and Akinsipo Oyelaja, OB and Familoni, O and Asekun, OT and Oladipo, SD and Osinubi, AD},
title = {Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer's disease treatment: molecular docking and molecular dynamic simulation studies.},
journal = {In silico pharmacology},
volume = {12},
number = {2},
pages = {80},
pmid = {39224128},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence expected to rise sharply in the coming years. Despite extensive research, effective treatments addressing the multifaceted pathophysiology of AD remain elusive. This study investigates the therapeutic potential of twenty-seven prolinamides (P1 - P27), with the focus on their interactions with key proteins implicated in AD pathogenesis. Four of the compounds, namely; 10-((4-nitrophenyl)prolyl)-10 H-phenothiazine (P14), 2-((4-nitrophenyl)prolyl)isoindoline (P19), 1-(4-formylphenyl)-N-(p-tolyl)pyrrolidine-2-carboxamide (P22), and N,1-bis(4-nitrophenyl)pyrrolidine-2-carboxamide (P27) showed promising potential as Alzheimer's drug. In-silico approaches including molecular docking, molecular dynamic (MD) simulation, post md study, physicochemical and drug-likeness parameters were employed to ascertain the potential of these compounds as inhibitors of certain proteins implicated in the pathophysiology of Alzheimer's disease. Molecular docking and dynamics simulations demonstrated that P14, P19, P22 and P27 exhibited promising binding affinities towards crucial AD-associated proteins, including Beta-Secretase 1 (BACE1), Butyrylcholinesterase (BuChE), and Tau-tubulin kinase 2 (TTBK2). Structural stability analyses revealed that prolinamides, particularly P22 and P27 for BACE1 and P14 and P19 for BuChE, exhibited greater stability than their reference ligands, indicated by lower RMSD, RoG, and RMSF values. For BuChE, Rivastigmine had a docking score of -7.0 kcal/mol, a binding free energy (ΔGbind) of -22.19 ± 2.44 kcal/mol, RMSD of 1.361 ± 0.162 Å, RMSF of 9.357 ± 3.212 Å, and RoG of 22.919 ± 0.064 Å, whereas P19 exhibited a superior docking score of -10.3 kcal/mol, a significantly better ΔGbind of -33.74 ± 2.84 kcal/mol, RMSD of 1.347 ± 0.132 Å, RMSF of 8.164 ± 2.748 Å, and RoG of 22.868 ± 0.070 Å. Physicochemical and pharmacokinetic assessments affirmed the drug-likeness and bioavailability of P19 notably capable of penetrating the blood-brain barrier. Compounds P19 and P22, emerged as multi-targeted ligands, offering the potential for simultaneous modulation of multiple AD-related pathways. These findings highlight the possibilities of these compounds to be explored as novel therapeutic agents for AD. They also highlight the need for further experimental validation to confirm their efficacy and safety profiles, advancing them toward clinical application in AD management.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-024-00250-z.},
}

@article {pmid39223908,
year = {2024},
author = {Jin, D and Zhang, M and Shi, L and Liu, H},
title = {Investigating the Impact of IL-6 and CXCL8 on Neurodegeneration and Cognitive Decline in Alzheimer's Disease.},
journal = {The international journal of neuropsychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijnp/pyae038},
pmid = {39223908},
issn = {1469-5111},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting the elderly, characterized by severe cognitive impairment and memory loss. Emerging evidence suggests that neuroinflammation plays a significant role in AD pathogenesis, with cytokines like interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL8) contributing to the disease progression.

METHODS: We utilized GEO datasets to identify IL-6 and CXCL8 as pivotal inflammatory markers in AD. In vitro experiments were conducted using SK-N-BE(2)-M17 and THP-1 cell lines treated with IL-6 and CXCL8 to model AD. Additionally, in vivo tests on Amyloid Precursor Protein/Presenilin 1 (APP/PS1) AD mouse models were performed to assess the impact of these cytokines on cognitive functions and brain pathology.

RESULTS: The results indicated a significant decrease in cell viability, increased apoptosis, and elevated inflammatory factor secretion following IL-6 and CXCL8 treatment in vitro. In vivo, AD mouse models treated with these cytokines exhibited exacerbated emotional distress, decreased social interaction, impaired cognitive functions, and increased amyloid protein deposition in neural tissues.

CONCLUSIONS: The study highlights the detrimental effects of IL-6 and CXCL8 on neuronal health and cognitive functions in AD. These findings suggest that targeting these cytokines could offer potential therapeutic interventions for improving patient outcomes in Alzheimer's disease.},
}

@article {pmid39223743,
year = {2024},
author = {Singh, A and Sinha, S and Singh, NK},
title = {Dietary Natural Flavonoids: Intervention for MAO-B Against Parkinson's Disease.},
journal = {Chemical biology & drug design},
volume = {104},
number = {3},
pages = {e14619},
doi = {10.1111/cbdd.14619},
pmid = {39223743},
issn = {1747-0285},
mesh = {*Parkinson Disease/drug therapy/metabolism ; *Monoamine Oxidase/metabolism ; Humans ; *Flavonoids/chemistry/pharmacology/therapeutic use ; *Monoamine Oxidase Inhibitors/pharmacology/therapeutic use/chemistry ; Animals ; Dopamine/metabolism ; Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; },
abstract = {Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches.},
}

*Parkinson Disease/drug therapy/metabolism
*Monoamine Oxidase/metabolism
Humans
*Flavonoids/chemistry/pharmacology/therapeutic use
*Monoamine Oxidase Inhibitors/pharmacology/therapeutic use/chemistry
Animals
Dopamine/metabolism
Neuroprotective Agents/pharmacology/chemistry/therapeutic use

@article {pmid39223564,
year = {2024},
author = {Hwang, JW and Kim, J and Park, JH and Nam, J and Jang, JY and Jo, A and Lee, HJ and Hoe, HS},
title = {Felodipine attenuates neuroinflammatory responses and tau hyperphosphorylation through JNK/P38 signaling in tau-overexpressing AD mice.},
journal = {Molecular brain},
volume = {17},
number = {1},
pages = {62},
pmid = {39223564},
issn = {1756-6606},
support = {24-BR-02-03//KBRI/ ; 24-BR-02-12//KBRI/ ; 23-BR-05-02//KBRI/ ; 24-BR-03-01//KBRI/ ; 24-BR-03-07//KBRI/ ; CCL22061-100//NST/ ; H0301-24-1001//NIPA/ ; },
mesh = {Animals ; *tau Proteins/metabolism ; Phosphorylation/drug effects ; *Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Felodipine/pharmacology/therapeutic use ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Microglia/drug effects/metabolism/pathology ; MAP Kinase Signaling System/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; },
abstract = {We previously demonstrated that felodipine, an L-type calcium channel blocker, inhibits LPS-mediated neuroinflammatory responses in BV2 microglial cells and wild-type mice. However, the effects of felodipine on tau pathology, a hallmark of Alzheimer's disease (AD), have not been explored yet. Therefore, in the present study, we determined whether felodipine affects neuroinflammation and tau hyperphosphorylation in 3-month-old P301S transgenic mice (PS19), an early phase AD mice model for tauopathy. Felodipine administration decreased tauopathy-mediated microglial activation and NLRP3 expression in PS19 mice but had no effect on tauopathy-associated astrogliosis. In addition, felodipine treatment significantly reduced tau hyperphosphorylation at S202/Thr205 and Thr212/Ser214 residues via inhibiting JNK/P38 signaling in PS19 mice. Collectively, our results suggest that felodipine significantly ameliorates tau hyper-phosphorylation and tauopathy-associated neuroinflammatory responses in AD mice model for tauopathy and could be a novel therapeutic agent for AD.},
}

Animals
*tau Proteins/metabolism
Phosphorylation/drug effects
*Mice, Transgenic
*Neuroinflammatory Diseases/drug therapy/metabolism
*Felodipine/pharmacology/therapeutic use
*Alzheimer Disease/pathology/drug therapy/metabolism
*p38 Mitogen-Activated Protein Kinases/metabolism
*Microglia/drug effects/metabolism/pathology
MAP Kinase Signaling System/drug effects
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Mice
Disease Models, Animal
Mice, Inbred C57BL

@article {pmid39222666,
year = {2024},
author = {Sundaram, ASM and Mofatteh, M and Ashraf, GM and Praticò, D},
title = {Glymphotherapeutics for Alzheimer's disease: time to move the needle.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102478},
doi = {10.1016/j.arr.2024.102478},
pmid = {39222666},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), the most predominant neurodegenerative disease and a quintessential entity within the dementia umbrella, is a global public health crisis. While the lack of disease modifying therapies has been a weak point in AD treatment, the success of recently approved monoclonal antibody-based therapeutics (aducanumab and lecanemab) targeted at the removal of amyloid-beta (Aβ) peptides in the brain is still under debate. There are multiple safety concerns about these approved neurotherapeutics including amyloid-related imaging abnormalities, stroke, meningitis, encephalitis, and even death. Novel paradigms focused on aquaporin-4-mediated neuro-perivascular Aβ and Tau protein clearance pathway are garnering attention. In this paper, we argue that orchestrating the drug discovery focused on glymphatic clearance-facilitating drugs ("glymphotherapeutics") might be a potentially novel and viable strategy to mitigate the progression and improve the clinical outcomes of AD.},
}

@article {pmid34465922,
year = {2021},
author = {Granholm, AC and Ledreux, A},
title = {Biomarkers show value of studying dementia in Down syndrome.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {10},
pages = {599-600},
pmid = {34465922},
issn = {1759-4766},
support = {R01 AG071228/AG/NIA NIH HHS/United States ; RF1 AG061566/AG/NIA NIH HHS/United States ; R21 AG048631/AG/NIA NIH HHS/United States ; P01 AG014449/AG/NIA NIH HHS/United States ; R21 AG056974/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Biomarkers ; *Down Syndrome/complications/diagnosis ; Humans ; },
abstract = {More than 90% of people with Down syndrome develop Alzheimer disease but receive little or no treatment for their dementia. Novel biomarkers of ageing and dementia bring new hope to this medically vulnerable population and can also help researchers understand dementia in other populations.},
}

*Alzheimer Disease/diagnosis
Amyloid beta-Peptides
Biomarkers
*Down Syndrome/complications/diagnosis
Humans

@article {pmid39222549,
year = {2024},
author = {Kim, MJ and Kim, MH and Kim, S and Lee, JJ and Kim, HJ},
title = {Near-infrared laser diode mitigates Aβ1-42-induced neurodegeneration in cortical neurons.},
journal = {Journal of photochemistry and photobiology. B, Biology},
volume = {259},
number = {},
pages = {113021},
doi = {10.1016/j.jphotobiol.2024.113021},
pmid = {39222549},
issn = {1873-2682},
abstract = {Alzheimer's disease, a prevalent neurodegenerative condition primarily affecting older adults, remains incurable. Its principle pathological hallmark is the accelerated accumulation of amyloid β (Aβ) protein. This study investigates the potential of photobiomodulation using near infrared light to counteract Aβ1-42-induced synaptic degeneration and neurotoxicity. We focused on the effect of 808 nm near-infrared laser diode (LD) on Aβ1-42 cytotoxicity in primary cultured cortical neurons. We assessed cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, observing substantial benefits from LD irradiation with a power of 10 mW and a dose of 30 J. Cells exposed to Aβ1-42 exhibited morphological changes indicative of synaptic damage and a significant decrease in the number of postsynaptic density protein-95 (PSD-95) contacts, which were significantly improved with near-infrared LD therapy. Furthermore, this therapy reduced Aβ and phosphorylated tau (P-tau) protein accumulation. Additionally, near-infrared LD irradiation substantially lessened the Aβ1-42-induced rise in glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) in astrocytes and microglia. Remarkably, near-infrared LD irradiation effectively inhibited phosphorylation of key proteins involved in Aβ1-42-induced necroptosis, namely Receptor-interacting protein kinase-3 (RIP3) and Mixed Lineage Kinase domain-Like protein (MLKL). Our findings suggest that near-infrared LD treatment significantly reduces neurodegeneration by reducing glial overactivation and neuronal necroptosis triggered by Aβ1-42. Thus, near-infrared LD treatment emerges as a promising approach for slowing or treating Alzheimer's disease, offering new avenues in its management.},
}

@article {pmid39221402,
year = {2024},
author = {Guanín Cabrera, CL and Jaramillo, AP and Vallejo, MP and Cueva, MG and Grandes, X and Navarro Grijalva, M and Hidalgo Guerrero, OJ},
title = {Navigating Prevention: A Systematic Review of Strategies for Alzheimer's Disease in High-Risk and Affected Individuals.},
journal = {Cureus},
volume = {16},
number = {8},
pages = {e65972},
pmid = {39221402},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) remains a widespread cause of dementia globally, and its prevalence is increasing due to the aging population. Two key pathologies typically identify this neurodegenerative disease process: the accumulation of amyloid plaques and the formation of neurofibrillary tangles containing hyperphosphorylated tau. Diagnosis relies on the patient's clinical presentation meeting specific criteria, along with the use of fluid and imaging biomarkers. The current treatment focuses on addressing symptoms, with ongoing trials aiming to decrease the production and overall impact of brain pathology. Here, we explore various methods to minimize the risks of AD in patients and individuals at high risk of developing it. To address this, we carefully selected 10 articles that discuss various prevention methods used today to promote brain health, including diets that are believed to have neuroprotective properties. The study findings emphasize the importance of further strengthening the evidence and conducting larger randomized controlled trials to gain a better understanding of the potential benefits for individuals at high risk of developing AD, as well as those already diagnosed with it.},
}

@article {pmid39220822,
year = {2024},
author = {Yakkundi, A and Gupta, R and Ramesh, K and Verma, A and Khan, U and Ansari, MA},
title = {Implications of Convolutional Neural Network for Brain MRI Image Classification to Identify Alzheimer's Disease.},
journal = {Parkinson's disease},
volume = {2024},
number = {},
pages = {6111483},
pmid = {39220822},
issn = {2090-8083},
abstract = {Alzheimer's disease is a chronic clinical condition that is predominantly seen in age groups above 60 years. The early detection of the disease through image classification aids in effective diagnosis and suitable treatment. The magnetic resonance imaging (MRI) data on Alzheimer's disease have been collected from Kaggle which is a freely available data source. These datasets are divided into training and validation sets. The present study focuses on training MRI datasets using TinyNet architecture that suits small-scale image classification problems by overcoming the disadvantages of large convolutional neural networks. The architecture is designed such that convergence time is reduced and overall generalization is improved. Though the number of parameters used in this architecture is lesser than the existing networks, still this network can provide better results. Training MRI datasets achieved an accuracy of 98% with the method used with a 2% error rate and 80% for the validation MRI datasets with a 20% error rate. Furthermore, to validate the model-supporting data collected from Kaggle and other open-source platforms, a comparative analysis is performed to substantiate TinyNet's applicability and is projected in the discussion section. Transfer learning techniques are employed to infer the differences and to improve the model's efficiency. Furthermore, experiments are included for fine-tuning attempts at the TinyNet architecture to assess how the nuances in convolutional neural networks have an impact on its performance.},
}

@article {pmid39219949,
year = {2024},
author = {Singhal, M and Modi, N and Bansal, L and Abraham, J and Mehta, I and Ravi, A},
title = {The Emerging Role of Neurosteroids: Novel Drugs Brexanalone, Sepranolone, Zuranolone, and Ganaxolone in Mood and Neurological Disorders.},
journal = {Cureus},
volume = {16},
number = {7},
pages = {e65866},
pmid = {39219949},
issn = {2168-8184},
abstract = {This review investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Notably, these disorders encompass postpartum depression, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), epilepsy, and Alzheimer's disease. Brexanolone and zuranolone have emerged as frontrunners in the treatment of postpartum depression, offering rapid relief from debilitating symptoms. Their mechanism of action involves modulation of the gamma-aminobutyric acid (GABA) system, which plays a pivotal role in mood regulation. Clinical trials have demonstrated their efficacy, heralding a potential breakthrough in addressing this often-overlooked condition. In the context of PTSD and MDD, neurosteroids have demonstrated significant promise. Their positive allosteric modulation of GABA-A receptors translates into improved mood stabilization and reduced symptoms. This novel approach represents a departure from conventional treatments and could offer newfound hope for individuals grappling with these disorders. Beyond mood disorders, neurosteroids, especially ganaxalone, exhibit potential in the realm of epilepsy management. Ganaxalone's capacity to control seizures is attributed to its GABAergic activity, which helps restore the delicate balance of neurotransmission in epileptic brains. Moreover, neurosteroids have revealed neuroprotective properties in Alzheimer's disease models. By influencing the GABAergic system, they mitigate excitotoxicity, a hallmark of Alzheimer's pathology. This neuroprotection opens a novel avenue for slowing neurodegeneration, although further research and clinical validation are essential. In conclusion, this review underscores the substantial therapeutic promise of neurosteroids in mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains.},
}

@article {pmid39219118,
year = {2024},
author = {Lai, JQ and Xu, YN},
title = {Small Bowel Obstruction Caused by a Rare Foreign Body: A Case Report and Literature Review.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056339263240826103827},
pmid = {39219118},
issn = {1573-4056},
abstract = {BACKGROUND: Ingestion of gastrointestinal foreign bodies (FB) is a common clinical problem worldwide. Approximately 10-20% of FBs require an endoscopic procedure for removal, and < 1% require surgery.

CASE DESCRIPTION: An 89-year-old male with Alzheimer's disease was hospitalized because of abdominal pain, abdominal distention, vomiting for three days, and cessation of bowel movements for six days. Abdominal computed tomography (CT) scan showed a small intestinal obstruction and an atypical FB in the small intestine. A pill and remaining plastic casing were removed from the small intestine during surgery. FB is a square with four sharp acute angles at its edge. The patient was discharged after two weeks of treatment, and no recurrence or complications were observed during the 6- month follow-up.

CONCLUSION: Atypical intestinal FBs may cause misdiagnosis and easily lead to serious complications. Therefore, an appropriate radiological examination, such as CT, is necessary for unexplained intestinal obstruction. Symptomatic intestinal FBs should be actively removed to avoid serious complications.

@article {pmid39218406,
year = {2024},
author = {Atanasova, M and Stavrakov, G and Philipova, I and Georgiev, B and Bastida, J and Doytchinova, I and Berkov, S},
title = {AChE inhibitory activity of N-substituted natural galanthamine derivatives.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {129937},
doi = {10.1016/j.bmcl.2024.129937},
pmid = {39218406},
issn = {1464-3405},
abstract = {Galanthamine derivatives are known for their AChE inhibitory activity. Among them, galanthamine has been approved for treatment of Alzheimer's disease. N-acetylnorgalanthamine (narcisine) and N-(2'-methyl)allylnorgalanthamine (the most potent natural AChE inhibitor of galanthamine type) were synthetized using N-norgalanthamine as a precursor. The NMR data described previously for narcisine were revised by two-dimensional [1]H-[1]H and [1]H-[13]C chemical shift correlation experiments. AChE inhibitory assays showed that N-acetylnorgalanthamine and N-formylnorgalanthamine (with previously unknown activity) are 4- and 43-times, respectively, less potent than galanthamine. In vitro (AChE inhibitory) and in silico (docking, ADME) assays and comparison of N-(2'-methyl)allylnorgalanthamine with galanthamine prove that this molecule is a very promising natural AChE inhibitor (33-times more potent than galanthamine) which further in vivo studies would provide better estimation about its applicability as a drug.},
}

@article {pmid39218292,
year = {2024},
author = {Hu, J and Liu, X and Wang, J and Yang, Q and Li, W and Yang, J and Zhang, W and Zeng, L and Li, S},
title = {Improvement of olfactory function in AD mice mediated by immune responses under 40 Hz light flickering.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {137958},
doi = {10.1016/j.neulet.2024.137958},
pmid = {39218292},
issn = {1872-7972},
abstract = {BACKGROUND: 40 Hz light flickering has shown promise as a non-invasive therapeutic approach for alleviating both pathological features and cognitive impairments in Alzheimer's disease (AD) model mice and AD patients. Additionally, vision may influence olfactory function through cross-modal sensory interactions.

OBJECTIVE: To investigate the impact of 40 Hz light flickering on olfactory behavior in AD model mice and to explore the underlying mechanisms of this intervention.

METHODS: We used immunofluorescence techniques to observe the activation of the olfactory bulb (OB) in C57BL/6J mice under 40 Hz light flickering. A buried food test was conducted to evaluate olfactory behavior in AD mice. Additionally, RNA sequencing (RNA-seq) technology was employed to detect transcriptional alterations in the OBs of AD mice following light stimulation.

RESULTS: 40 Hz light flickering was found to effectively activate the OB. This stimulation led to enhanced olfactory behavior and did not alter P-tau protein mRNA levels within the OBs of AD mice. RNA sequencing revealed significant transcriptional changes in the OBs under flickering, particularly related to immune responses.

CONCLUSION: Vision can influence olfactory function through cross-modal sensory interactions in rodent models. 40 Hz light stimulation improved olfactory performance in AD mice. However, the improvement in olfaction in AD mice is not related to changes in P-tau mRNA levels. Instead, it may be associated with an altered immune response, providing a scientific basis for the clinical treatment of olfactory disorders in Alzheimer's disease.},
}

@article {pmid39218080,
year = {2024},
author = {Li, J and Liu, Y and Yin, C and Zeng, Y and Mei, Y},
title = {Structural and functional remodeling of neural networks in β-amyloid driven hippocampal hyperactivity.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102468},
doi = {10.1016/j.arr.2024.102468},
pmid = {39218080},
issn = {1872-9649},
abstract = {Early detection of Alzheimer's disease (AD) is essential for improving the patients outcomes and advancing our understanding of disease, allowing for timely intervention and treatment. However, accurate biomarkers are still lacking. Recent evidence indicates that hippocampal hyperexcitability precedes the diagnosis of AD decades ago, can predict cognitive decline. Thus, could hippocampal hyperactivity be a robust biomarker for early-AD, and what drives hippocampal hyperactivity in early-AD? these critical questions remain to be answered. Increasing clinical and experimental studies suggest that early hippocampal activation is closely associated with longitudinal β-amyloid (Aβ) accumulation, Aβ aggregates, in turn, enhances hippocampal activity. Therefore, in this narrative review, we discuss the role of Aβ-induced altered intrinsic neuronal properties as well as structural and functional remodeling of glutamatergic, GABAergic, cholinergic, noradrenergic, serotonergic circuits in hippocampal hyperactivity. In addition, we analyze the available therapies and trials that can potentially be used clinically to attenuate hippocampal hyperexcitability in AD. Overall, the present review sheds lights on the mechanism behind Aβ-induced hippocampal hyperactivity, and highlights that hippocampal hyperactivity could be a robust biomarker and therapeutic target in prodromal AD.},
}

@article {pmid39217860,
year = {2024},
author = {You, H and Song, Y and Yang, Y and Wang, X and Pan, S and Huang, J and Shao, Q and Shi, D and Li, B and Li, J and Li, X},
title = {Rational design of a high-affinity fluorescent probe for visualizing monitoring the amyloid β clearance effect of anti-Alzheimer's disease drug candidates.},
journal = {European journal of medicinal chemistry},
volume = {278},
number = {},
pages = {116800},
doi = {10.1016/j.ejmech.2024.116800},
pmid = {39217860},
issn = {1768-3254},
abstract = {Beta-amyloid (Aβ), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aβ aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aβ in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aβ changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aβ-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aβ elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aβ plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aβ distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aβ plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aβ levels in preclinical therapeutic assessments.},
}

@article {pmid39217739,
year = {2024},
author = {Wehrli, JM and Xia, Y and Meister, L and Tursunova, S and Kleim, B and Bach, DR and Quednow, BB},
title = {Forget me not: The effect of doxycycline on human declarative memory.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {89},
number = {},
pages = {1-9},
doi = {10.1016/j.euroneuro.2024.08.006},
pmid = {39217739},
issn = {1873-7862},
abstract = {Investigations into neuroprotective drugs are in high demand for the treatment of neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, but also psychiatric disorders, such as depression, trauma, and substance use. One potential drug class being investigated are tetracyclines impacting on a variety of neuroprotective mechanisms. At the same time, tetracyclines like doxycycline have been suggested to affect human fear and spatial memory as well as reducing declarative memory retention. Based on the assumed necessity for synaptic consolidation in hippocampus-dependent learning, we hypothesised declarative memory may be similarly impaired by doxycycline as fear and spatial memory. Therefore, in this study we investigate the potential diminishing effects of doxycycline on consolidation of declarative memory in healthy humans. Additionally, to test for effect specificity we assessed motor memory, sustained attention, and processing speed. We administered a neuropsychological test battery in three independent randomized placebo-controlled double-blind trials (RCTs), in which healthy young volunteers (total N = 252) either received a single oral dose doxycycline (200 mg, n = 126) or placebo (n = 126) in a between-subject design. We found no evidence for a detrimental effect of doxycycline on declarative memory; instead, doxycycline improved declarative learning (p-value=0.022, Cohen's d=0.15) and memory consolidation (p=0.040, d=0.26). Contrarily, doxycycline slightly reduced motor learning (p=0.001, d=0.10) but subtly strengthened long-term motor memory (p=0.001, d=0.10). These results suggest that doxycycline can improve declarative learning and memory without having long term negative effects on other cognitive domains in healthy humans. Our results give hope to further investigate doxycycline in neuroprotective treatment applications.},
}

@article {pmid39216535,
year = {2024},
author = {Forny Germano, L and Koehler, JA and Baggio, LL and Cui, F and Wong, CK and Rittig, N and Cao, X and Matthews, D and Drucker, DJ},
title = {The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice.},
journal = {Molecular metabolism},
volume = {},
number = {},
pages = {102019},
doi = {10.1016/j.molmet.2024.102019},
pmid = {39216535},
issn = {2212-8778},
abstract = {OBJECTIVE: The development of glucagon-like peptide-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has been accompanied by evidence for anti-inflammatory and cytoprotective actions in the heart, blood vessels, kidney, and brain. Whether GLP-1R agonists might be useful clinically for attenuating deterioration of cognitive dysfunction and reducing the progression of Alzheimer's disease remains uncertain.

METHODS: Here we evaluated the actions of semaglutide and tirzepatide, clinically distinct GLP-1 medicines, in two mouse models of neurodegeneration.

RESULTS: Semaglutide reduced body weight and improved glucose tolerance in 12-month-old male and female 5XFAD and APP/PS1 mice, consistent with pharmacological engagement of the GLP-1R. Nevertheless, amyloid plaque density was not different in the cerebral cortex, hippocampus, or subiculum of semaglutide-treated 12-month-old 5XFAD and APP/PS1 mice. IBA1 and GFAP expression were increased in the hippocampus of 5XFAD and APP/PS1 mice but were not reduced by semaglutide. Moreover, parameters of neurobehavioral and cognitive function evaluated using Open Field testing or the Morris water maze were not improved following treatment with semaglutide. To explore whether incretin therapies might be more effective in younger mice, we studied semaglutide and tirzepatide action in 6-month-old male and female 5XFAD mice. Neither semaglutide or tirzepatide modified the extent of plaque accumulation, hippocampal IBA1+ or GFAP+ cells, or parameters of neurobehavioral testing, despite improving glucose tolerance and reducing body weight. mRNA biomarkers of inflammation and neurodegeneration were increased in the hippocampus of male and female 5XFAD mice but were not reduced after treatment with semaglutide or tirzepatide.

CONCLUSIONS: Collectively, these findings reveal preservation of the metabolic actions of two GLP-1 medicines, semaglutide and tirzepatide, yet inability to detect improvement in structural and functional parameters of neurodegeneration in two mouse models of Alzheimer's disease.},
}

@article {pmid39215579,
year = {2024},
author = {Zelek, WM and Bevan, RJ and Nimmo, J and Dewilde, M and De Strooper, B and Morgan, BP},
title = {Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae278},
pmid = {39215579},
issn = {1460-2156},
abstract = {Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury in Alzheimer's disease and other neurodegenerative diseases. Here, we investigate the impact of brain delivery of a complement-blocking antibody on neurodegeneration in an Alzheimer's mouse model. We engineered a brain-penetrant recombinant antibody targeting the pro-inflammatory membrane attack complex. Systemic administration of this antibody in APPNL-G-F mice reduced brain levels of complement activation products, demonstrating successful brain entry and target engagement. Prolonged treatment decreased synapse loss, amyloid burden and brain inflammatory cytokine levels, concomitant with cognitive improvement compared to controls. These results underscore the potential of brain-penetrant complement-inhibiting drugs as promising therapeutics, targeting downstream of amyloid plaques in Alzheimer's disease.},
}

@article {pmid39215550,
year = {2024},
author = {Goerges, G and Disse, P and Peischard, S and Ritter, N and Brenker, C and Seebohm, G and Strutz-Seebohm, N and Schreiber, JA},
title = {Evaluation of SK-N-SH Cells as a Model for NMDA Receptor Induced Toxicity.},
journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology},
volume = {58},
number = {4},
pages = {431-444},
doi = {10.33594/000000722},
pmid = {39215550},
issn = {1421-9778},
support = {IMF SC-112107//IMF (Innovative Medizinische Forschung) https://www.medizin.uni-muenster.de/imf/das-imf//Germany ; },
mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; Humans ; *Cell Survival/drug effects ; *Ketamine/pharmacology ; Cell Line, Tumor ; *Glutamic Acid/metabolism/toxicity ; Cell Differentiation/drug effects ; Neurons/drug effects/metabolism/cytology/pathology ; Nerve Tissue Proteins ; },
abstract = {BACKGROUND/AIMS: Over the years, the number of patients with neurodegenerative diseases is constantly rising illustrating the need for new neuroprotective drugs. A promising treatment approach is the reduction of excitotoxicity induced by rising (S)-glutamate levels and subsequent NMDA receptor overactivation. To facilitate the search for new NMDA receptor inhibitors neuronal cell models are needed. In this study, we evaluated the suitability of human SK-N-SH cells to serve as a cell model for neurodegeneration induced by NMDA receptor overstimulation.

METHODS: The cytoprotective effect of the unselective NMDA receptor blocker ketamine as well as the GluN2B-selective inhibitor WMS14-10 was evaluated utilizing different cell viability assays, such as endpoint (LDH, CCK-8, DAPI/FACS) and time dependent methods (bioimpedance).

RESULTS: Non-differentiated as well as differentiated SK-N-SH cells express GluN1 and GluN2B subunits. Furthermore, 50 mM (S)-glutamate led to an instantaneous decrease in cell survival. Only application of unselective channel blocker ketamine could protect differentiated cells against this effect, while the selective inhibitor WMS14-10 did not significantly increase cell survival.

CONCLUSION: SK-N-SH cells show an increased sensitivity to (S)-glutamate mediated cytotoxicity with higher differentiation level, that is only partially induced by NMDA receptor overstimulation. Furthermore, we showed that only unselective NMDA receptor inhibition can partially reverse (S)-glutamate-induced toxicity.},
}

*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors
Humans
*Cell Survival/drug effects
*Ketamine/pharmacology
Cell Line, Tumor
*Glutamic Acid/metabolism/toxicity
Cell Differentiation/drug effects
Neurons/drug effects/metabolism/cytology/pathology
Nerve Tissue Proteins

@article {pmid39215523,
year = {2024},
author = {Salooja, CM and Sanker, A and Deepthi, K and Jereesh, AS},
title = {An ensemble approach for circular RNA-disease association prediction using variational autoencoder and genetic algorithm.},
journal = {Journal of bioinformatics and computational biology},
volume = {},
number = {},
pages = {2450018},
doi = {10.1142/S0219720024500185},
pmid = {39215523},
issn = {1757-6334},
abstract = {Circular RNAs (circRNAs) are endogenous non-coding RNAs with a covalently closed loop structure. They have many biological functions, mainly regulatory ones. They have been proven to modulate protein-coding genes in the human genome. CircRNAs are linked to various diseases like Alzheimer's disease, diabetes, atherosclerosis, Parkinson's disease and cancer. Identifying the associations between circular RNAs and diseases is essential for disease diagnosis, prevention, and treatment. The proposed model, based on the variational autoencoder and genetic algorithm circular RNA disease association (VAGA-CDA), predicts novel circRNA-disease associations. First, the experimentally verified circRNA-disease associations are augmented with the synthetic minority oversampling technique (SMOTE) and regenerated using a variational autoencoder, and feature selection is applied to these vectors by a genetic algorithm (GA). The variational autoencoder effectively extracts features from the augmented samples. The optimized feature selection of the genetic algorithm effectively carried out dimensionality reduction. The sophisticated feature vectors extracted are then given to a Random Forest classifier to predict new circRNA-disease associations. The proposed model yields an AUC value of 0.9644 and 0.9628 under 5-fold and 10-fold cross-validations, respectively. The results of the case studies indicate the robustness of the proposed model.},
}

@article {pmid39215494,
year = {2024},
author = {Gibson, AW and Elser, H and Rosso, M and Cornblath, EJ and Fonkeu, Y and Prasad, S and Rothstein, A and Nasrallah, IM and Wolk, DA and Guo, MH},
title = {Ischemic stroke associated with amyloid-related imaging abnormalities in a patient treated with lecanemab.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14223},
pmid = {39215494},
issn = {1552-5279},
support = {//University of Pennsylvania Alzheimer's Disease Research Center: Christopher Clark Scholars Award/ ; R25 NS065745/NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION: Anti-amyloid antibody therapies such as lecanemab are increasingly being used to treat Alzheimer's disease (AD). These therapies are associated with a high rate of amyloid-related imaging abnormalities (ARIA).

METHODS: We review the case history of a patient who developed ARIA associated with lecanemab treatment.

RESULTS: In addition to microhemorrhages and cerebral edema that are recognized features of ARIA, the patient developed several ischemic strokes. The patient also experienced frequent electrographic seizures without overt clinical seizures. The patient demonstrated clinical and radiographic improvement after steroid treatment.

DISCUSSION: Our case suggests that ischemic strokes may be a feature of ARIA and highlights the importance of having a high clinical suspicion for seizures in ARIA. As anti-amyloid therapies are likely going to be increasingly used to treat AD, it is important to appreciate the spectrum of clinical and radiographic findings that can result as side effects from this class of therapies.

HIGHLIGHTS: We report a patient who developed severe amyloid-related imaging abnormalities (ARIA) after treatment with lecanemab. Our report suggests that ischemic strokes may be a novel imaging feature of ARIA. Our report highlights the need for high clinical suspicion for seizures in ARIA.},
}

@article {pmid39215261,
year = {2024},
author = {Zhang, R and Huang, X and Zhou, C and Zhang, Q and Jia, D and Xie, X and Zhang, J},
title = {Network pharmacology-based mechanism analysis of dauricine on the alleviating Aβ-induced neurotoxicity in Caenorhabditis elegans.},
journal = {BMC complementary medicine and therapies},
volume = {24},
number = {1},
pages = {321},
pmid = {39215261},
issn = {2662-7671},
support = {No. 226Z2801G//the central government guides local science and technology development fund projects of Hebei Province/ ; No. 226Z2801G//the central government guides local science and technology development fund projects of Hebei Province/ ; No. B2022005014//the postdoctoral research project of Hebei Province/ ; No.C21R0803, C22R0802//Science and technology innovation project of Hebei Academy of Agriculture and Forestry Sciences/ ; H2020207002//Natural Science Foundation of Hebei Province/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Network Pharmacology ; *Molecular Docking Simulation ; *Amyloid beta-Peptides/metabolism ; *Benzylisoquinolines/pharmacology ; Alzheimer Disease/drug therapy ; Disease Models, Animal ; Animals, Genetically Modified ; Tetrahydroisoquinolines ; },
abstract = {BACKGROUND: Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer's disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment.

METHODS: Network pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU.

RESULTS: There are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of "compound-target-biological process-pathway network". Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by Aβ aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin T（Th-T）staining experiment revealed that DAU decreased Aβ accumulation in AD nematodes. Further experiments also confirmed DAU's protein scavenging activity in polyglutamine (polyQ) aggregation nematodes.

CONCLUSION: Collectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of Aβ aggregation and the restoration of protein homeostasis.},
}

Animals
*Caenorhabditis elegans/drug effects
*Network Pharmacology
*Molecular Docking Simulation
*Amyloid beta-Peptides/metabolism
*Benzylisoquinolines/pharmacology
Alzheimer Disease/drug therapy
Disease Models, Animal
Animals, Genetically Modified
Tetrahydroisoquinolines

@article {pmid39214953,
year = {2024},
author = {Qu, L and Xu, S and Lan, Z and Fang, S and Xu, Y and Zhu, X},
title = {Apolipoprotein E in Alzheimer's Disease: Focus on Synaptic Function and Therapeutic Strategy.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39214953},
issn = {1559-1182},
support = {81971009//the National Nature Science Foundation of China/ ; 81920108017//the National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Provincial Medical Key Discipline/ ; ZKX22025//Nanjing Medical Science and Technology Development Foundation/ ; ZD0211800//the STI2030-Major Projects-2022/ ; },
abstract = {Synaptic dysfunction is a critical pathological feature in the early phase of Alzheimer's disease (AD) that precedes typical hallmarks of AD, including beta-amyloid (Aβ) plaques and neurofibrillary tangles. However, the underlying mechanism of synaptic dysfunction remains incompletely defined. Apolipoprotein E (APOE) has been shown to play a key role in the pathogenesis of AD, and the ε4 allele of APOE remains the strongest genetic risk factor for sporadic AD. It is widely recognized that APOE4 accelerates the development of Aβ and tau pathology in AD. Recent studies have indicated that APOE affects synaptic function through a variety of pathways. Here, we summarize the mechanism of modulating synapses by various APOE isoforms and demonstrate the therapeutic potential by targeting APOE4 for AD treatment.},
}

@article {pmid39214859,
year = {2024},
author = {Pfitzer, J and Pinky, PD and Perman, S and Redmon, E and Cmelak, L and Suppiramaniam, V and Coric, V and Qureshi, IA and Gramlich, MW and Reed, MN},
title = {Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.16215},
pmid = {39214859},
issn = {1471-4159},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.},
}

@article {pmid39214819,
year = {2024},
author = {Moussavi, Z and Uehara, M and Rutherford, G and Lithgow, B and Millikin, C and Wang, X and Saha, C and Mansouri, B and Omelan, C and Fellows, L and Fitzgerald, PB and Koski, L},
title = {Corrigendum to "Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial" [Neurotherapeutics 21 (3) (2024) e00331].},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {100438},
doi = {10.1016/j.neurot.2024.100438},
pmid = {39214819},
issn = {1878-7479},
}

@article {pmid39214332,
year = {2024},
author = {Yang, X and Tohda, C},
title = {Diosgenin upregulates axonal guidance partner molecules, Galectin-1 and Secernin-1.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {137954},
doi = {10.1016/j.neulet.2024.137954},
pmid = {39214332},
issn = {1872-7972},
abstract = {Galectin-1, a β-galactosides-binding protein, is widely expressed in various tissues and exhibits diverse biological activities. We previously obtained following findings; 1) Diosgenin, a steroid sapogenin, promoted axonal regeneration in the brain and recovered memory deficits in a model of Alzheimer's disease (AD), 5XFAD mouse; 2) Neuron-specific overexpression of Galectin-1 protein in the hippocampus recovered memory impairment and promoted axonal regeneration in the brain in 5XFAD mice; 3) Secernin-1, a counterpart and axonal guidance molecule for Galectin-1-expressing axons, was secreted from the prefrontal cortical neurons to promote axonal guidance from the hippocampus to the prefrontal cortex. However, it has never been elucidated that diosgenin signaling increase Galectin-1 and Secernin-1 or not. Here, we found that diosgenin treatment upregulated the protein level of Galectin-1 in the hippocampus both in primary cultured neurons and in 5XFAD mouse brains. In addition, diosgenin-induced upregulation of Galectin-1 was diminished by treatment of a neutralizing antibody of 1,25D3-membrane-associated rapid response steroid-binding receptor (1,25D3-MARRS), a direct binding receptor for diosgenin. Importantly, knockdown of Galectin-1 in hippocampal neurons inhibited axonal growth activity of diosgenin. Furthermore, the expression level of Secernin-1 was also increased in prefrontal cortical neurons by administration of diosgenin to 5XFAD mice. These findings suggest that diosgenin is a suitable compound to facilitate Galectin-1-Secernin-1-mediated axonal growth in the AD brain.},
}

@article {pmid39214327,
year = {2024},
author = {Zhang, QX and Zhang, LJ and Zhao, N and Yang, L},
title = {Irisin in ischemic Stroke, Alzheimer's disease and Depression: A narrative review.},
journal = {Brain research},
volume = {},
number = {},
pages = {149192},
doi = {10.1016/j.brainres.2024.149192},
pmid = {39214327},
issn = {1872-6240},
abstract = {Irisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Irisin is widely involved in the regulation of glucose and lipid metabolism. In addition, recent studies have demonstrated that Irisin can inhibit inflammation, restrain oxidative stress and have neuroprotective effects, which suggests that Irisin may have a good therapeutic effect on central nervous system diseases. Therefore, this review summarizes the role of Irisin in central nervous system diseases, including its signal pathways and possible mechanisms, etc. Irisin may be a potential candidate drug for the treatment of central nervous system diseases.},
}

@article {pmid39214326,
year = {2024},
author = {Chen, J and Zhang, M and Shen, Z and Tang, M and Zeng, Y and Bai, D and Zhao, P and Jiang, G},
title = {Low-dose diazepam improves cognitive function in APP/PS1 mouse models: Involvement of AMPA receptors.},
journal = {Brain research},
volume = {},
number = {},
pages = {149207},
doi = {10.1016/j.brainres.2024.149207},
pmid = {39214326},
issn = {1872-6240},
abstract = {Previous studies have indicated a close association between cognitive impairment in patients with neurodegenerative diseases, such as Alzheimer's disease (AD), and synaptic damage. Diazepam (DZP), a benzodiazepine class drug, is used to control symptoms such as seizures, anxiety, and sleep disorders. These symptoms can potentially manifest throughout the entire course of AD. Therefore, DZP may be utilized in the treatment of AD to manage these symptoms. However, the specific role and mechanisms of DZP in AD remain unclear. In this study, we discovered that long-term administration of a low dose of DZP (0.5 mg/kg) improved cognitive function and protected neurons from damage in APP/PS1 mice. Mechanistic investigations revealed that DZP exerted its neuroprotective effects and reduced Aβ deposition by modulating GluA1 (glutamate AMPA receptor subunit) to influence synaptic function. In conclusion, these findings highlight the potential benefits of DZP as a novel therapeutic approach, suggesting that long-term use of low-dose DZP in early-stage AD patients may be advantageous in slowing disease progression.},
}

@article {pmid39214273,
year = {2024},
author = {Shi, H and Zhao, Y},
title = {Astaxanthin inhibits apoptosis in a cell model of tauopathy by attenuating endoplasmic reticulum stress and unfolded protein response.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176962},
doi = {10.1016/j.ejphar.2024.176962},
pmid = {39214273},
issn = {1879-0712},
abstract = {The accumulation of misfolded proteins is a common pathological characteristic shared by many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. The disruption of proteostasis triggers endoplasmic reticulum (ER) stress, during which the unfolded protein response (UPR) is initiated by activation of protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6). These three branches of UPR signals act in concert to reduce the levels of abnormal proteins and restore ER homeostasis. However, the overactivation of UPR impairs cell function and induces apoptosis, which has been implicated in neurodegeneration. Astaxanthin is a xanthophyll carotenoid which has been shown to have neuroprotective effects in both cell and animal models; however, its effects on ER stress and UPR induced by disrupted proteostasis remain unclear. In this study, the effects of astaxanthin on ER stress and cytotoxicity were investigated in N2a cells stably expressing the pro-aggregant tau repeat domain carrying FTDP-17 mutation ΔK280 (Tau4RDΔK280). The results demonstrated that astaxanthin significantly inhibited Tau4RDΔK280-induced loss of cell viability and apoptosis, attenuating Tau4RDΔK280-induced caspase-3 activation and decrease of Bcl-2. Further studies revealed that astaxanthin treatment alleviated Tau4RDΔK280-induced ER stress and suppressed the activation of PERK, IRE1 and ATF6 signaling pathways. These findings suggested that astaxanthin might inhibit Tau4RDΔK280-induced cytotoxicity by attenuating UPR and ER stress. In addition, astaxanthin treatment resulted in a great reduction in the production of intracellular reactive oxygen species and a significant decrease in calcium influx induced by Tau4RDΔK280, which also contributed to the protective effects of astaxanthin against Tau4RDΔK280-induced cytotoxicity.},
}

@article {pmid39213084,
year = {2024},
author = {Solingapuram Sai, KK and Erichsen, JM and Gollapelli, KK and Krizan, I and Miller, M and Bansode, A and Jorgensen, MJ and Register, T and Cazzola, C and Gandhi, R and Suman, J and Craft, S},
title = {First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {101},
number = {1},
pages = {309-320},
doi = {10.3233/JAD-240484},
pmid = {39213084},
issn = {1875-8908},
mesh = {Animals ; *Administration, Intranasal ; *Insulin/pharmacokinetics/administration & dosage ; Tissue Distribution ; *Brain/metabolism/diagnostic imaging ; *Positron-Emission Tomography/methods ; Gallium Radioisotopes/administration & dosage/pharmacokinetics ; Chlorocebus aethiops ; Male ; Heterocyclic Compounds, 1-Ring/pharmacokinetics/administration & dosage ; Heterocyclic Compounds/pharmacokinetics/administration & dosage ; Female ; Positron Emission Tomography Computed Tomography/methods ; Radiopharmaceuticals/pharmacokinetics/administration & dosage ; },
abstract = {BACKGROUND: Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes.

OBJECTIVE: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system.

METHODS: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans.

RESULTS: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq.

CONCLUSIONS: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.},
}

Animals
*Administration, Intranasal
*Insulin/pharmacokinetics/administration & dosage
Tissue Distribution
*Brain/metabolism/diagnostic imaging
*Positron-Emission Tomography/methods
Gallium Radioisotopes/administration & dosage/pharmacokinetics
Chlorocebus aethiops
Male
Heterocyclic Compounds, 1-Ring/pharmacokinetics/administration & dosage
Heterocyclic Compounds/pharmacokinetics/administration & dosage
Female
Positron Emission Tomography Computed Tomography/methods
Radiopharmaceuticals/pharmacokinetics/administration & dosage

@article {pmid39213078,
year = {2024},
author = {Nagata, T and Nakajima, S and Kito, S and Shinagawa, S},
title = {The Association Between Distinct Delusional Ideations and Depressive Symptoms in Alzheimer's Disease: A Re-Analysis of CATIE-AD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240702},
pmid = {39213078},
issn = {1875-8908},
abstract = {BACKGROUND: Delusional ideations, one of neuropsychiatric symptoms (NPSs), are frequently shown in the long-term progression of Alzheimer's disease (AD), and comorbid with other NPSs including depression or agitation. Despite various types of delusional ideations, the comorbidity between each delusional ideation and depressive symptoms has not been discussed.

OBJECTIVE: The present cross-sectional study is aimed at testing the hypothetical mechanism of comorbid pattern in AD.

METHODS: Among 421 patients with AD, we analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease to compare age, sex, racial type, Mini-Mental State Examination (MMSE) scores, and Neuropsychiatric Inventory (NPI) depression score of between the presence and absence of each delusional ideation (delusion of persecution, theft, jealousy, abandonment, phantom boarder, Capgras syndrome, misidentification of place, or television sign). Next, with the stratification based on MMSE score of < or > = 15 points, we further explored association between delusional ideation and depressive symptom that was found significances in the primary analysis.

RESULTS: Among eight subtypes of delusional ideations, depression score was higher in those with persecution delusion or Capgras syndrome. Moreover, the Capgras syndrome was associated with presence of depression in severer global cognitive impairment status.

CONCLUSIONS: As comorbid NPSs of delusional ideation in AD, depressive severity is associated with specific delusional subtype: persecution delusion and Capgras syndrome. Capgras syndrome may be attributable to severe cognitive impairment in addition to depressive symptom. The consideration of pathogenetic differences in the distinct delusional ideations may be helpful for clinicians to select the treatment strategy.},
}

@article {pmid39213075,
year = {2024},
author = {Yang, J and Ran, K and Ma, W and Chen, Y and Chen, Y and Zhang, C and Ye, H and Lu, Y and Ran, C},
title = {Degradation of Amyloid-β Species by Multi-Copper Oxidases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240625},
pmid = {39213075},
issn = {1875-8908},
abstract = {BACKGROUND: Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored.

OBJECTIVE: To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment.

METHODS: We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices.

RESULTS: We discovered that CP, an important MCO in human blood, could degrade Aβ peptides. We also found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus.

CONCLUSIONS: To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.},
}

@article {pmid39213065,
year = {2024},
author = {Huynh, ALH and Wang, Y and Ma, L and Low, YLC and Chen, W and Fowler, C and Tan, ECK and Masters, CL and Jin, L and Pan, Y and , },
title = {A Comparison of an Australian Observational Longitudinal Alzheimer's Disease Cohort to Community-Based Australian Data.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240241},
pmid = {39213065},
issn = {1875-8908},
abstract = {BACKGROUND: Observational Alzheimer's disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied.

OBJECTIVE: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia.

METHODS: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities.

RESULTS: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation - AIBL 79±7 years, PBS/census 81±7, p < 0.001, dementia/census 83±8, p < 0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p = 0.020, dementia/census 29%, p < 0.001; CALD - AIBL 3%, PBS/census 20%, p < 0.001, dementia/census 22%, p < 0.001).

CONCLUSIONS: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD.},
}

@article {pmid39212742,
year = {2024},
author = {Chen, C and Novakovic, A and Jamsen, K and Vong, C and Arshad, U},
title = {Sparse item testing of clinical scales in neurology trials to alleviate burden to patients.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {39212742},
issn = {1432-1459},
abstract = {BACKGROUND: Neurology trials typically rely on composite scales for measuring symptom severity. Completing all items in a long scale can be burdensome for patients, caregivers, and trial personnel.

OBJECTIVES: To test the hypothesis that sparse item testing, aided by item-response modelling, can preserve the power for detecting treatment effect in a controlled trial.

METHODS: UPDRS (Unified Parkinson's Disease Rating Scale) Part III (motor examinations) data from a placebo-controlled trial (N = 391) of ropinirole were analysed with a longitudinal item-response model. Symptom severity was estimated directly from item scores as a latent variable, without needing the total score. This enabled sparse item testing. With the symptom severity as a clinical endpoint, the potential power loss for detecting treatment effect due to the sparse testing was assessed by simulation.

RESULTS: When each patient took 18 of all 27 tests in UPDRS Part III at each study visit, there was no appreciable power loss. Reducing four visits to three also had negligible effects on power. A threefold reduction of the total tests that each patient needed to do throughout the trial, from 108 to 27, only compromised power slightly, e.g., from 92 to 87% at N = 160.

CONCLUSIONS: These findings show that using the symptom severity derived from item scores as the endpoint allows sparse testing to drastically reduce trial burden without incurring major power loss. This benefit would multiply for indications like Alzheimer's disease where modern trials often require patients to be tested on multiple scales at several times.},
}

@article {pmid39212516,
year = {2024},
author = {Imran, S and Ahmad, W and Saltanat, S},
title = {Therapeutic Evaluation of Unani Medicine, Including Single Drugs and Polyherbal Formulations with Special Reference to Neurodegenerative Disorders.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {39212516},
issn = {1078-6791},
abstract = {Unani remedies are considered safe and can be utilized as a healthcare resource due to the adverse effects of conventional pharmaceuticals. For instance, Donepezil, used to treat alzhemier's disease exerts many adverse effects such as dizziness, vertigo, dryness of mouth. Similarly, Memantine used to slow the neurotoxicity involved in alzhemier's disease also exerts adverse effects like vomiting, tremors and sleep disturbance. Over sixty percent of drugs are derived from synthetic basis, highlighting the potential benefits of natural Unani treatments as a safer alternative. Neurodegenerative disorders are illnesses characterized by structural and functional deterioration due to abnormal protein aggregation, resulting in inflammation and oxidative stress in the central nervous system. In unani system of medicine all current brain ailments, including alzheimer's disease, parkinson's disease, mania, anxiety, melancholia and others are classified under the general category of neurodegenerative disorders Their pathogenic variables and soociated symptoms and therapeutic modalities are similar. This study focuses on evidence-based Unani herbs and polyherbal formulations for the treatment of various neurodegenerative disorders. It reveals that 43 ethnomedicinal plants can be employed to treat the symptoms of neurodegenerative disorders. The material was gathered from several sources that tabulated the specific details of individual herbs and polyherbal formulations and highlighted the importance of various phytoconstituents on neuroprotective action. The research provides in vivo and scientific evidence to support the use of ethnomedicine in treating neurodegenerative disorders.

AIM OF THE STUDY: This study aims to validate the efficacy of Unani medicines, traditionally used for neurodegenerative diorders through evidence-based research.

METHODS: To scan single and polyherbal formulations for neurodegenerative disorders, a literature review of traditional Unani medicine texts was conducted. To collect evidence on the efficacy of these indicated medications in the treatment of neurodegenerative disorders, electronic resources such as ScienceDirect, PubMed, Wiley Online Library, and Google Scholar were searched. The current study is a systematic review that applies inclusion and exclusion criteria rooted in the classical symptoms of neurological disorders. It evaluates the efficacy of individual herbs and polyherbal formulations recommended by Unani scholars for treatment perspectives.

RESULTS: The researchers have so far discovered 43 single drugs and 38 polyherbal formulations in Unani classical literature for treating various neurodegenerative disorders. These herbs have antioxidant, anti-Alzheimer's, anti-Parkinsonism, anti-convulsant, cognitive enhancer, anti-anxiety, neuroprotective, and anti-depressant properties, with clinical investigations proving their efficacy. The study exclusively focuses on systematic review, highlighting selected clinical studies to assess their quality and reliability of evidence. These are discussed in the introduction to provide context and understanding.

CONCLUSIONS: After a thorough review of entire literature of Unani medicine, it is evident that has painstakingly focused more on physiopathology of diseases of Dimāgh wa A'sāb including their treatment protocols .These protocols include Istifrāgh (biopurification), Taskhīn (producing warmth), Tajfiīf (desiccation), Tafrīħ-i Taba' (exhilaration). Research into Unani medicine has shown promising results, particularly in the use of medicinal plants known for their neuroprotective properties. One of the key advantages of Unani herbs is their natural composition, which typically consists of bioactive compounds that exert neuroprotective effects without the harsh impact often associated with synthetic drugs. For instance, herbs like Brahmi(Bacopa monnieri), Waj Turki (Acorus calamus), Chilghoza(Pinus gerardiana Wall) and Asgand (Withania somnifera) and many other plants have been studied for their ability to enhance cognitive function, reduce oxidative stress, and support neuronal health. These herbs work through various mechanisms such as antioxidant activity, anti-inflammatory properties, and modulation of neurotransmitter levels, all of which contribute to their neuroprotective potential. Nevertheless some of the compound formulations presented, that, have not yet undergone clinical testing. As a result, the researchers are advised to validate those medicines that have not yet undergone clinical evaluation.},
}

@article {pmid39211791,
year = {2024},
author = {Shao, Y and Xu, J and Chen, W and Hao, M and Liu, X and Zhang, R and Wang, Y and Dong, Y},
title = {miR-135b: An emerging player in cardio-cerebrovascular diseases.},
journal = {Journal of pharmaceutical analysis},
volume = {14},
number = {10},
pages = {100997},
doi = {10.1016/j.jpha.2024.100997},
pmid = {39211791},
issn = {2214-0883},
abstract = {miR-135 is a highly conserved miRNA in mammals and includes miR-135a and miR-135b. Recent studies have shown that miR-135b is a key regulatory factor in cardio-cerebrovascular diseases. It is involved in regulating the pathological process of myocardial infarction, myocardial ischemia/reperfusion injury, cardiac hypertrophy, atrial fibrillation, diabetic cardiomyopathy, atherosclerosis, pulmonary hypertension, cerebral ischemia/reperfusion injury, Parkinson's disease, and Alzheimer's disease. Obviously, miR-135b is an emerging player in cardio-cerebrovascular diseases and is expected to be an important target for the treatment of cardio-cerebrovascular diseases. However, the crucial role of miR-135b in cardio-cerebrovascular diseases and its underlying mechanism of action has not been reviewed. Therefore, in this review, we aimed to comprehensively summarize the role of miR-135b and the signaling pathway mediated by miR-135b in cardio-cerebrovascular diseases. Drugs targeting miR-135b for the treatment of diseases and related patents, highlighting the importance of this target and its utility as a therapeutic target for cardio-cerebrovascular diseases, have been discussed.},
}

@article {pmid39211279,
year = {2024},
author = {Kumar, S and Song, K and Wang, J and Baghel, MS and Wong, P and Cao, X and Wan, M},
title = {Serum Amyloid P Secreted by Bone Marrow Adipocytes Drives Skeletal Amyloidosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.15.608092},
pmid = {39211279},
issn = {2692-8205},
abstract = {The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer's disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and is sufficient to promote the formation of insoluble amyloid deposits from soluble Aβ peptides in in vitro and ex vivo 3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aβ peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.},
}

@article {pmid39211245,
year = {2024},
author = {Thorwald, MA and Godoy-Lugo, JA and Santa Maria, N and Chakhoyan, A and O'Day, P and Jacobs, R and Zlokovic, B and Finch, C},
title = {Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.14.607970},
pmid = {39211245},
issn = {2692-8205},
abstract = {BACKGROUND: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports.

OBJECTIVE: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice.

METHODS: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot.

RESULTS: DFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%.

CONCLUSIONS: WT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.},
}

@article {pmid39210432,
year = {2024},
author = {Wang, H and Li, S and Zhang, J and Peng, W and Li, T and Zhang, J},
title = {Efficacy of selective serotonin reuptake inhibitors-related antidepressants in Alzheimer's disease: a meta-analysis.},
journal = {European journal of medical research},
volume = {29},
number = {1},
pages = {438},
pmid = {39210432},
issn = {2047-783X},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Selective Serotonin Reuptake Inhibitors/therapeutic use/adverse effects ; Antidepressive Agents/therapeutic use/adverse effects ; Citalopram/therapeutic use/adverse effects ; Sertraline/therapeutic use/adverse effects ; },
abstract = {OBJECTIVE: To study the effects of selective serotonin reuptake inhibitors (SSRIs) on cognitive functions, mental improvements, and adverse effects in patients with Alzheimer's disease (AD).

METHODS: Registered in INPLASY (INPLASY202450004), five drugs (citalopram, s-citalopram, quetiapine, olanzapine, and sertraline) were selected as representatives. A comprehensive search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 15, 2024. Search terms were combined using Boolean operators, specifically 'AND' between different categories (e.g., 'Alzheimer's Disease' AND 'SSRIs') and 'OR' within the same category (e.g., 'citalopram OR s-citalopram OR quetiapine OR olanzapine OR sertraline'), to ensure a thorough retrieval of relevant studies. The selection followed rigorous inclusion and exclusion criteria for meta-analysis.

RESULTS: Fourteen articles from 1118 were selected for meta-analysis. The indicators, including Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Brief Psychiatric Rating Scale (BPRS), and Cornell Scale for Depression in Dementia (CSDD), were used to assess the effects of the drugs on AD treatment. According to the results of NPI, CSDD, BPRS, MMSE, and security assessments, the five antidepressants have significant advantages in AD treatment compared with placebo, while the MMSE of the patient treated with the antidepressants did not show notable changes compared with patients treated only with placebo. Statistical analyses were conducted using Review Manager 5.3, employing random-effects models to account for study heterogeneity and sensitivity analyses to test the robustness of our findings.

CONCLUSION: This study suggests that SSRI-related antidepressants have great potential values in AD treatment, and further research on the application of SSRI-related antidepressants in AD treatment is necessary.},
}

*Alzheimer Disease/drug therapy
Humans
*Selective Serotonin Reuptake Inhibitors/therapeutic use/adverse effects
Antidepressive Agents/therapeutic use/adverse effects
Citalopram/therapeutic use/adverse effects
Sertraline/therapeutic use/adverse effects

@article {pmid39209323,
year = {2024},
author = {Joshi, N and Vaidya, B and Sharma, SS},
title = {Transient receptor potential channels as an emerging target for the treatment of Alzheimer's disease: Unravelling the potential of pharmacological interventions.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bcpt.14073},
pmid = {39209323},
issn = {1742-7843},
support = {DST/CSRI/2021/633//Cognitive Science Research Initiative, Department of Science & Technology (DST), New Delhi, India/ ; //Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt. of India/ ; },
abstract = {Alzheimer's disease (AD) is a devastating disorder with a multifaceted aetiology characterized by dementia, which later progresses to cognitive impairment. Significant efforts have been made to develop pharmacological interventions that slow down the pathogenesis of AD. However, conventional drugs have failed to satisfactorily treat AD and are more focussed towards symptomatic management. Thus, there is a gap in the literature regarding novel targets and modulators targeting them for the effective treatment of AD. Recent studies have demonstrated that modulation of transient receptor potential (TRP) channels has the potential to halt AD pathogenesis at an early stage and rescue hippocampal neurons from death. Amongst several members, TRP channels like TRPA1, TRPC6, TRPM2 and TRPV2 have shown promising results in the attenuation of neurobehavioural cognitive deficits as well as signalling pathways governing such cognitive decline. Furthermore, as these channels govern the ionic balance in the cell, their beneficial effects have also been known to maintain the homeostasis of Ca[2+], which is the major culprit eliciting the vicious cycle of excitotoxicity, mitochondrial dysfunction, ROS generation and neurodegeneration. Despite such tremendous potential of TRP channel modulators, their clinical investigation remains elusive. Therefore, in the present review, we have discussed such agents in the light of TRP channels as molecular targets for the amelioration of AD both at the preclinical and clinical levels.},
}

@article {pmid39208968,
year = {2024},
author = {Chen, S and Han, C and Wang, X and Zhang, Q and Yang, X},
title = {Alantolactone improves cognitive impairment in rats with Porphyromonas gingivalis infection by inhibiting neuroinflammation, oxidative stress, and reducing Aβ levels.},
journal = {Brain research},
volume = {1845},
number = {},
pages = {149203},
doi = {10.1016/j.brainres.2024.149203},
pmid = {39208968},
issn = {1872-6240},
abstract = {Neuroinflammation caused by the chronic periodontal pathogen Porphyromonas gingivalis is growing regarded as as a key factor in the pathogenesis of Alzheimer's disease (AD). Alantolactone (AL), a sesquiterpene lactone isolated from the root of Inula racemosa Hook. f, has been proven to provide various neuroprotective effects. However, whether AL can improve cognitive impairment caused by P. gingivalis infection remains unclear. In this research, a rat model of P. gingivalis infection was used to examine the neuroprotective benefits of AL. The results revealed that 6 weeks of AL treatment (50 and 100 mg/kg) shortened escape latency and increased the number of crossings over the platform location and time spent in the target quadrant of P. gingivalis-infected rats in the Morris water maze experiment. By activating the Nrf2/HO-1 pathway, AL suppressed malondialdehyde (MDA) levels and simultaneously increased the activity of total superoxide dismutase (T-SOD). Furthermore, AL lowered the presence of IL-6, IL-1β, and TNFα in the hippocampal and cortical tissues of P. gingivalis-infected rats by inhibiting astrocyte and microglial activation and NF-κB phosphorylation. AL also significantly reduced Aβ levels in the cortical and hippocampus tissues of rats infected with P. gingivalis. In conclusion, AL improved cognitive impairment in P. gingivalis-infected rats by inhibiting neuroinflammation, reducing Aβ1-42 level, and exerting antioxidative stress effects.},
}

@article {pmid39208367,
year = {2024},
author = {Anastassiadis, C and Martinez-Valbuena, I and Vasilevskaya, A and Thapa, S and Hadian, M and Morales-Rivero, A and Mora-Fisher, D and Salvo, C and Taghdiri, F and Sato, C and Moreno, D and Anor, CJ and Misquitta, K and Couto, B and Tang-Wai, DF and Lang, AE and Fox, SH and Rogaeva, E and Kovacs, GG and Tartaglia, MC},
title = {CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders.},
journal = {Neurology},
volume = {103},
number = {6},
pages = {e209818},
doi = {10.1212/WNL.0000000000209818},
pmid = {39208367},
issn = {1526-632X},
mesh = {Humans ; *alpha-Synuclein/cerebrospinal fluid ; Female ; Male ; Aged ; Middle Aged ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; *Amyloid beta-Peptides/cerebrospinal fluid ; Parkinsonian Disorders/cerebrospinal fluid/diagnosis ; Supranuclear Palsy, Progressive/cerebrospinal fluid/diagnosis ; Peptide Fragments/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; },
abstract = {BACKGROUND AND OBJECTIVES: There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and β-amyloid (Aβ) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies.

METHODS: This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records.

RESULTS: We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aβ42 levels (β = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aβ42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01).

DISCUSSION: We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aβ42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.},
}

Humans
*alpha-Synuclein/cerebrospinal fluid
Female
Male
Aged
Middle Aged
*Biomarkers/cerebrospinal fluid
Cross-Sectional Studies
*Amyloid beta-Peptides/cerebrospinal fluid
Parkinsonian Disorders/cerebrospinal fluid/diagnosis
Supranuclear Palsy, Progressive/cerebrospinal fluid/diagnosis
Peptide Fragments/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid
Alzheimer Disease/cerebrospinal fluid/diagnosis
Aged, 80 and over

@article {pmid39208251,
year = {2024},
author = {Malek, R and Sałat, K and Totoson, P and Karcz, T and Refouvelet, B and Skrzypczak-Wiercioch, A and Maj, M and Simakov, A and Martin, H and Siwek, A and Szałaj, N and Godyń, J and Panek, D and Więckowska, A and Jozwiak, K and Demougeot, C and Kieć-Kononowicz, K and Chabchoub, F and Iriepa, I and Marco-Contelles, J and Ismaili, L},
title = {Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00341},
pmid = {39208251},
issn = {1948-7193},
abstract = {At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.},
}

@article {pmid39207717,
year = {2024},
author = {Ling, Y and Crotti, A},
title = {Emerging Microglial Therapies and Targets in Clinical Trial.},
journal = {Advances in neurobiology},
volume = {37},
number = {},
pages = {623-637},
pmid = {39207717},
issn = {2190-5215},
mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; },
abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.},
}

*Microglia/metabolism
Humans
Clinical Trials as Topic
Neurodegenerative Diseases/drug therapy/therapy/metabolism
Nervous System Diseases/drug therapy/metabolism

@article {pmid39206899,
year = {2024},
author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z},
title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {29},
number = {8},
pages = {291},
doi = {10.31083/j.fbl2908291},
pmid = {39206899},
issn = {2768-6698},
support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; },
mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; },
abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.},
}

*Ferroptosis/physiology
Humans
*Neurodegenerative Diseases/metabolism/physiopathology
*Iron/metabolism
Animals
Neurons/metabolism/pathology

@article {pmid39206477,
year = {2024},
author = {Saffour, S and Evrim Evren, A and Saglik, BN and Yurttas, L},
title = {Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673333159240815061359},
pmid = {39206477},
issn = {1875-533X},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes.

METHODS: The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman's spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted.

RESULTS: Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 μM, 0.096 μM, and 0.177 μM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied.

CONCLUSION: Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer's disease.},
}

@article {pmid39204887,
year = {2024},
author = {Visitsattapongse, S and Maneerat, A and Trinavarat, A and Rattanabannakit, C and Morkphrom, E and Senanarong, V and Srinonprasert, V and Songsaeng, D and Atchaneeyasakul, LO and Pintavirooj, C},
title = {Feature-Based Classification of Mild Cognitive Impairment and Alzheimer's Disease Based on Optical Coherence Tomographic Angiographic Image.},
journal = {Sensors (Basel, Switzerland)},
volume = {24},
number = {16},
pages = {},
doi = {10.3390/s24165192},
pmid = {39204887},
issn = {1424-8220},
support = {D1671, and (IO)R016438003//Siriraj Foundation and Siriraj research development fund/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/classification/pathology ; *Cognitive Dysfunction/diagnostic imaging/diagnosis ; *Tomography, Optical Coherence/methods ; Angiography/methods ; Machine Learning ; Male ; Aged ; Female ; },
abstract = {Alzheimer's disease is a type of neurodegenerative disorder that is characterized by the progressive degeneration of brain cells, leading to cognitive decline and memory loss. It is the most common cause of dementia and affects millions of people worldwide. While there is currently no cure for Alzheimer's disease, early detection and treatment can help to slow the progression of symptoms and improve quality of life. This research presents a diagnostic tool for classifying mild cognitive impairment and Alzheimer's diseases using feature-based machine learning applied to optical coherence tomographic angiography images (OCT-A). Several features are extracted from the OCT-A image, including vessel density in five sectors, the area of the foveal avascular zone, retinal thickness, and novel features based on the histogram of the range-filtered OCT-A image. To ensure effectiveness for a diverse population, a large local database for our study was collected. The promising results of our study, with the best accuracy of 92.17,% will provide an efficient diagnostic tool for early detection of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/diagnostic imaging/classification/pathology
*Cognitive Dysfunction/diagnostic imaging/diagnosis
*Tomography, Optical Coherence/methods
Angiography/methods
Machine Learning
Male
Aged
Female

@article {pmid39204336,
year = {2024},
author = {Londhe, SG and Walhekar, V and Shenoy, M and Kini, SG and Scotti, MT and Scotti, L and Kumar, D},
title = {Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3β to Combat Alzheimer's Disease.},
journal = {Pharmaceutics},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/pharmaceutics16080991},
pmid = {39204336},
issn = {1999-4923},
abstract = {BACKGROUND: Alzheimer's disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer's disease. Co-targeting GSK3β and BChE in Alzheimer's disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer's disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE.

METHODS: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger.

RESULTS: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of -9.6 and -12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study.

CONCLUSION: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer's disease, capable of simultaneously inhibiting both GSK-3β and BuChE.},
}

@article {pmid39204144,
year = {2024},
author = {Sivasinprasasn, S and Tocharus, J and Mahatheeranont, S and Nakrat, S and Tocharus, C},
title = {Anthocyanin-Rich Fraction of Black Rice Bran Extract Protects against Amyloid β-Induced Oxidative Stress, Endoplasmic Reticulum Stress, and Neuronal Apoptosis in SK-N-SH Cells.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {8},
pages = {},
doi = {10.3390/ph17081039},
pmid = {39204144},
issn = {1424-8247},
support = {FF66/066//Fundamental Fund 2023, Chiang Mai University/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population. An accumulation of amyloid plaques and neurofibrillary tangles causes degeneration of neurons, leading to neuronal cell death. The anthocyanin-rich fraction of black rice (Oryza sativa L. variety "Luem Pua") bran (AFBRB), extracted using a solution of ethanol and water and fractionated using Amberlite XAD7HP column chromatography, contains a high anthocyanin content (585 mg of cyanidin-3-O-glucoside and 24 mg of peonidin-3-O-glucoside per gram of the rich extract), which has been found to reduce neurodegeneration. This study focused on the neuroprotective effects of AFBRB in Aβ25-35-induced toxicity in the human neuroblastoma cell line (SK-N-SH). SK-N-SH was exposed to Aβ25-35 (10 µM) to induce an AD cell model in vitro. Pretreatment with AFBRB (0.1, 1, or 10 µg/mL) or C3G (20 µM) was conducted for 2 h prior to the treatment with Aβ25-35 (10 µM) for an additional 24 h. The results indicate that AFBRB can protect against the cytotoxic effect of Aβ25-35 through attenuation of intracellular ROS production, downregulation of the expression of the proteins Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3, upregulation of the expression of Bcl-2 in the mitochondrial death pathway, and reduction in the expression of the three major markers of ER stress pathways in similar ways. Interestingly, we found that pretreatment with AFBRB significantly alleviated Aβ-induced oxidative stress, ER stress, and apoptosis in SK-N-SH cells. This suggests that AFBRB might be a potential therapeutic agent in preventing neurodegenerative diseases.},
}

@article {pmid39204110,
year = {2024},
author = {Zhou, X and Zhu, Z and Kuang, S and Huang, K and Li, Y and Wang, Y and Chen, H and Hoi, MPM and Xu, B and Yang, X and Zhang, Z},
title = {Tetramethylpyrazine Nitrone (TBN) Reduces Amyloid β Deposition in Alzheimer's Disease Models by Modulating APP Expression, BACE1 Activity, and Autophagy Pathways.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {8},
pages = {},
doi = {10.3390/ph17081005},
pmid = {39204110},
issn = {1424-8247},
support = {82304465//National Natural Science Foundation of China/ ; 82073821//National Natural Science Foundation of China/ ; SL2023A03J01103//Guangzhou Science and Technology Programme/ ; 2022A1515011729//Natural Science Foundation of Guangdong Province/ ; JCYJ20200109150717745//Key Program of Shenzhen Basic Research/ ; 0023/2020/AFJ//Science and Technology Development Fund, Macau SAR/ ; MYRG2022-00248-ICMS//the University of Macau Research Grant/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.},
}

@article {pmid39204102,
year = {2024},
author = {Forsell, P and Parrado Fernández, C and Nilsson, B and Sandin, J and Nordvall, G and Segerdahl, M},
title = {Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {8},
pages = {},
doi = {10.3390/ph17080997},
pmid = {39204102},
issn = {1424-8247},
abstract = {Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer's disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer's disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function.},
}

@article {pmid39203005,
year = {2024},
author = {Nakashima, M and Suga, N and Yoshikawa, S and Matsuda, S},
title = {Caveolae with GLP-1 and NMDA Receptors as Crossfire Points for the Innovative Treatment of Cognitive Dysfunction Associated with Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {16},
pages = {},
doi = {10.3390/molecules29163922},
pmid = {39203005},
issn = {1420-3049},
mesh = {Humans ; *Receptors, N-Methyl-D-Aspartate/metabolism ; *Glucagon-Like Peptide 1/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/etiology ; Animals ; *Neurodegenerative Diseases/metabolism ; *Caveolae/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; },
abstract = {Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer's disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer's disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.},
}

Humans
*Receptors, N-Methyl-D-Aspartate/metabolism
*Glucagon-Like Peptide 1/metabolism
*Cognitive Dysfunction/metabolism/drug therapy/etiology
Animals
*Neurodegenerative Diseases/metabolism
*Caveolae/metabolism
Alzheimer Disease/metabolism
Signal Transduction

@article {pmid39202843,
year = {2024},
author = {Papagiouvannis, G and Theodosis-Nobelos, P and Rekka, EA},
title = {Trolox, Ferulic, Sinapic, and Cinnamic Acid Derivatives of Proline and GABA with Antioxidant and/or Anti-Inflammatory Properties.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {16},
pages = {},
doi = {10.3390/molecules29163763},
pmid = {39202843},
issn = {1420-3049},
mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Coumaric Acids/pharmacology/chemistry ; Animals ; *gamma-Aminobutyric Acid/metabolism ; *Cinnamates/pharmacology/chemistry ; *Proline/chemistry/pharmacology ; Rats ; Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Lipid Peroxidation/drug effects ; Chromans ; },
abstract = {Degenerative conditions, such as neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC50 as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC50 as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions.},
}

*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Coumaric Acids/pharmacology/chemistry
Animals
*gamma-Aminobutyric Acid/metabolism
*Cinnamates/pharmacology/chemistry
*Proline/chemistry/pharmacology
Rats
Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
Lipid Peroxidation/drug effects
Chromans

@article {pmid39202269,
year = {2024},
author = {Pădureanu, V and Dop, D and Caragea, DC and Rădulescu, D and Pădureanu, R and Forțofoiu, MC},
title = {Cardiovascular and Neurological Diseases and Association with Helicobacter Pylori Infection-An Overview.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {14},
number = {16},
pages = {},
doi = {10.3390/diagnostics14161781},
pmid = {39202269},
issn = {2075-4418},
abstract = {This article investigates the link between Helicobacter pylori (H. pylori) infection and cardiovascular and neurological disorders. Recent research suggests that H. pylori may play a role in cardiovascular diseases like atherosclerosis, myocardial infarction, and stroke, as well as neurological diseases including Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Cardiovascular Diseases: H. pylori induces endothelial dysfunction and chronic inflammation, promoting atherosclerotic plaque formation and other cardiac complications. High infection prevalence in cardiovascular patients implies that systemic inflammation from H. pylori accelerates disease progression. Eradication therapies combined with anti-inflammatory and lipid-lowering treatments may reduce cardiovascular risk. Neurological Diseases: H. pylori may contribute to Alzheimer's, multiple sclerosis, and Parkinson's through systemic inflammation, neuroinflammation, and autoimmune responses. Increased infection prevalence in these patients suggests bacterial involvement in disease pathogenesis. The eradication of H. pylori could reduce neuroinflammation and improve outcomes. Discussions and Future Research: Managing H. pylori infection in clinical practice could impact public health and treatment approaches. Further research is needed to clarify these relationships. Longitudinal and mechanistic studies are essential to fully understand H. pylori's role in these conditions. Conclusions: H. pylori infection is a potential risk factor for various cardiovascular and neurological conditions. Additional research is critical for developing effective prevention and treatment strategies. Targeted therapies, including H. pylori eradication combined with anti-inflammatory treatments, could improve clinical outcomes. These findings highlight the need for an integrated clinical approach to include H. pylori evaluation and treatment.},
}

@article {pmid39202248,
year = {2024},
author = {Singh, SG and Das, D and Barman, U and Saikia, MJ},
title = {Early Alzheimer's Disease Detection: A Review of Machine Learning Techniques for Forecasting Transition from Mild Cognitive Impairment.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {14},
number = {16},
pages = {},
doi = {10.3390/diagnostics14161759},
pmid = {39202248},
issn = {2075-4418},
support = {AdtU/Seed/2023/011//Assam down town University/ ; },
abstract = {Alzheimer's disease is a weakening neurodegenerative condition with profound cognitive implications, making early and accurate detection crucial for effective treatment. In recent years, machine learning, particularly deep learning, has shown significant promise in detecting mild cognitive impairment to Alzheimer's disease conversion. This review synthesizes research on machine learning approaches for predicting conversion from mild cognitive impairment to Alzheimer's disease dementia using magnetic resonance imaging, positron emission tomography, and other biomarkers. Various techniques used in literature such as machine learning, deep learning, and transfer learning were examined in this study. Additionally, data modalities and feature extraction methods analyzed by different researchers are discussed. This review provides a comprehensive overview of the current state of research in Alzheimer's disease detection and highlights future research directions.},
}