@article {pmid37768458,
year = {2023},
author = {Arkhipov, VI and Chernomorets, IY and Zhuikova, NS and Fedorov, DA and Pershina, EV},
title = {The Role of NMDA Receptor Subunits in the Effect of Memantine on the Brain of Healthy Animals.},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {37768458},
issn = {1573-8221},
abstract = {The non-competitive NMDA glutamate receptor antagonist memantine has neuroprotective properties and is the first non-cholinergic drug approved for the treatment of Alzheimer's disease. The purpose of this work was to test the hypothesis that injections of memantine to healthy animals can affect the subunit composition of NMDA receptors in the brain, which may explain the effects of its chronic administration. For this, the expression of subunits GluN1, GluN2A, GluN2B, and GluN2C was studied in the hippocampus and prefrontal cortex of rats after single or five subchronic injections of memantine. The results showed that the GluN2C subunit (GRIN2C) plays an important role in the effects of memantine; against the background of memantine treatment, the expression of this subunit markedly decreased in the prefrontal cortex, but not in the hippocampus, which significantly affected the excitation/inhibition balance in cortical structures.},
}

@article {pmid37768457,
year = {2023},
author = {Voronova, AD and Karsuntseva, EK and Stepanova, OV and Chadin, AV and Shishkina, VV and Andretsova, SS and Fursa, GA and Shport, SV and Reshetov, IV and Chekhonin, VP},
title = {Modeling of Alzheimer's Disease to Study the Efficacy of Cell Therapy (Review).},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {37768457},
issn = {1573-8221},
abstract = {We analyzed the main approaches to the modeling of Alzheimer's disease for studying the effectiveness of cell therapy. Recent advances in regenerative medicine in the field of neuroscience create prospects for the use of various cell preparations for the treatment of Alzheimer's disease. Experimental data on the use of neural stem/progenitor cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells in various models of Alzheimer's disease are presented. Of particular importance is the standardization of protocols. The use of a standardized protocol in modeling of Alzheimer's disease will allow a comparative analysis of the effectiveness and safety of treatment to identify the optimal cell preparation. The data obtained on experimental animals can form the basis for further preclinical and clinical studies of cell therapy for Alzheimer's disease.},
}

@article {pmid37767948,
year = {2023},
author = {Upadhyay, P and Tyagi, A and Agrawal, S and Kumar, A and Gupta, S},
title = {Bidirectional Effect of Triphala on Modulating Gut-Brain Axis to Improve Cognition in the Murine Model of Alzheimer's Disease.},
journal = {Molecular nutrition & food research},
volume = {},
number = {},
pages = {e2300104},
doi = {10.1002/mnfr.202300104},
pmid = {37767948},
issn = {1613-4133},
support = {Fileno.R.12014/20/2018//Department of Health Research, Ministry of Health and Family Welfare, Govt of India New Delhi/ ; },
abstract = {SCOPE: The emerging role of gut microbiota and their metabolites in the modulation of the gut-brain axis has received much attention as a new hope for the treatment of hard-to-treat chronic neurodegenerative diseases like Alzheimer's disease. The naturally occurring polyphenols can restore the gut-brain axis by modulating gut microbiota and brain neurotransmitters. The Indian traditional medicine Triphala, a rich source of polyphenols, has been used on humans based on Prakriti or disease conditions for many years.

METHODS AND RESULTS: In this study, the dual mode (morning and evening) action of Triphala is used to provide scientific evidence of its superior preventive and therapeutic efficacy in C57BL/6 and 5xFAD, APP/PS1 transgenic mouse model of Alzheimer's disease. The study observes that Triphala treatment has significantly improved cognitive function, by modulating the APP pathway, reducing inflammation, and restoring the gut-brain axis by increasing the gut microbiota phyla of Bacteroides, Proteobacteria, Actinobacteria, etc., involved in maintaining the gut homeostasis.

CONCLUSIONS: The study paves a new path for using dual modes of Triphala alone or in combination to treat incurable AD.},
}

@article {pmid37766832,
year = {2023},
author = {Hainsworth, AH and Arancio, O and Elahi, FM and Isaacs, JD and Cheng, F},
title = {PDE5 inhibitor drugs for use in dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {9},
number = {3},
pages = {e12412},
pmid = {37766832},
issn = {2352-8737},
abstract = {UNLABELLED: Alzheimer's disease and related dementias (ADRD) remain a major health-care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase-5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration-approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real-world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half-life, and off-target effects.

HIGHLIGHTS: Potent phosphodiesterase-5 (PDE5) inhibitors are in clinical use as vasodilators.In animals PDE5 inhibitors enhance synaptic function and cognitive ability.In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease.Licensed PDE5 inhibitors have potential for repurposing in dementia.Prospective clinical trials of PDE5 inhibitors are warranted.},
}

@article {pmid37765357,
year = {2023},
author = {Ververis, A and Kyriakou, S and Ioannou, K and Chatzopoulou, PS and Panayiotidis, MI and Plioukas, M and Christodoulou, K},
title = {Chemical Profiling and Antioxidant and Anti-Amyloid Capacities of Salvia fruticosa Extracts from Greece.},
journal = {Plants (Basel, Switzerland)},
volume = {12},
number = {18},
pages = {},
doi = {10.3390/plants12183191},
pmid = {37765357},
issn = {2223-7747},
support = {N/A//The Cyprus Institute of Neurology and Genetics/ ; },
abstract = {An increasingly common ailment in elderly persons is Alzheimer's disease (AD), a neurodegenerative illness. Present treatment is restricted to alleviating symptoms; hence, there is a requirement to develop an effective approach to AD treatment. Salvia fruticosa (SF) is a medicinal plant with a documented neuroprotective potential. To identify extracts of increased neuroprotectivity, we partitioned the methanolic extract of SF aerial parts from Greece into several fractions, by employing solvents of different polarities. The fractions were chemically identified and evaluated for their antioxidancy and anti-neurotoxic potential against amyloid beta peptides 25-35 (Aβ25-35). Carnosol and carnosic acid were among the prominent compounds, while all partitions showed significant antioxidant capacity, with the diethyl ether and ethyl acetate partitions being the most potent. These, along with the aqueous and the butanolic fractions, demonstrated statistically significant anti-neurotoxic potential. Thus, our findings further validate the neuroprotective potential of SF and support its ethnopharmacological usage as an antioxidant. The particular properties found define SF as a promising source for obtaining extracts or bioactive compounds, possibly beneficial for generating AD-related functional foods or medications. Finally, our results encourage plant extract partitioning for acquiring fractions of enhanced biological properties.},
}

@article {pmid37765284,
year = {2023},
author = {Chaparro, CIP and Simões, BT and Borges, JP and Castanho, MARB and Soares, PIP and Neves, V},
title = {A Promising Approach: Magnetic Nanosystems for Alzheimer's Disease Theranostics.},
journal = {Pharmaceutics},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/pharmaceutics15092316},
pmid = {37765284},
issn = {1999-4923},
support = {PTDC/BTM-MAT/2472/2021//Fundação para a Ciência e Tecnologia/ ; UID/CTM/50025//Fundação para a Ciência e Tecnologia/ ; SFRH/BD/148588/2019//Fundação para a Ciência e Tecnologia/ ; },
abstract = {Among central nervous system (CNS) disorders, Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and a major cause of dementia worldwide. The yet unclear etiology of AD and the high impenetrability of the blood-brain barrier (BBB) limit most therapeutic compounds from reaching the brain. Although many efforts have been made to effectively deliver drugs to the CNS, both invasive and noninvasive strategies employed often come with associated side effects. Nanotechnology-based approaches such as nanoparticles (NPs), which can act as multifunctional platforms in a single system, emerged as a potential solution for current AD theranostics. Among these, magnetic nanoparticles (MNPs) are an appealing strategy since they can act as contrast agents for magnetic resonance imaging (MRI) and as drug delivery systems. The nanocarrier functionalization with specific moieties, such as peptides, proteins, and antibodies, influences the particles' interaction with brain endothelial cell constituents, facilitating transport across the BBB and possibly increasing brain penetration. In this review, we introduce MNP-based systems, combining surface modifications with the particles' physical properties for molecular imaging, as a novel neuro-targeted strategy for AD theranostics. The main goal is to highlight the potential of multifunctional MNPs and their advances as a dual nanotechnological diagnosis and treatment platform for neurodegenerative disorders.},
}

@article {pmid37765259,
year = {2023},
author = {Ababei, DC and Bild, V and Macadan, I and Vasincu, A and Rusu, RN and Blaj, M and Stanciu, GD and Lefter, RM and Bild, W},
title = {Therapeutic Implications of Renin-Angiotensin System Modulators in Alzheimer's Dementia.},
journal = {Pharmaceutics},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/pharmaceutics15092290},
pmid = {37765259},
issn = {1999-4923},
support = {POCU/993/6/13/154722//project"Net4SCIENCE: Applied doctoral and postdoctoral research network in the fields of smart specialization Health and Bioeconomy"/ ; },
abstract = {The Renin-Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer's dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation's favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies.},
}

@article {pmid37765118,
year = {2023},
author = {Ipe, RS and Kumar, S and Benny, F and Jayan, J and Manoharan, A and Sudevan, ST and George, G and Gahtori, P and Kim, H and Mathew, B},
title = {A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/ph16091310},
pmid = {37765118},
issn = {1424-8247},
abstract = {Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson's disease (PD) and Alzheimer's disease (AD), are closely correlated with altered biogenic amine concentrations in the brain caused by MAO. Toxic byproducts of this oxidative breakdown, including hydrogen peroxide, reactive oxygen species, and ammonia, can cause oxidative damage and mitochondrial dysfunction in brain cells. Certain MAO-B blockers have been recognized as effective treatment options for managing neurological conditions, including AD and PD. There is still a pressing need to find potent therapeutic molecules to fight these disorders. However, the focus of neurodegeneration studies has recently increased, and certain compounds are now in clinical trials. Chromones are promising structures for developing therapeutic compounds, especially in neuronal degeneration. This review focuses on the MAO-B inhibitory potential of several synthesized chromones and their structural activity relationships. Concerning the discovery of a novel class of effective chromone-based selective MAO-B-inhibiting agents, this review offers readers a better understanding of the most recent additions to the literature.},
}

@article {pmid37765115,
year = {2023},
author = {Di Paolo, M and Corsi, F and Cerri, C and Bisti, S and Piano, I and Gargini, C},
title = {A Window to the Brain: The Retina to Monitor the Progression and Efficacy of Saffron Repron[®] Pre-Treatment in an LPS Model of Neuroinflammation and Memory Impairment.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/ph16091307},
pmid = {37765115},
issn = {1424-8247},
support = {Repron//BioArum/ ; },
abstract = {A mechanism shared by most neurodegenerative diseases, like Alzheimer's disease (AD) and Parkinson's disease (PD), is neuroinflammation. It has been shown to have a link between cognitive impairment and retinal function under neuroinflammatory conditions, confirming the essential role of the retina as a window to the brain. Here, we characterize a mouse model of LPS-induced neuroinflammation describing the parallel deterioration of both memory and visual function. Then, we demonstrate, using the Novel Object Recognition test (NOR) and electroretinogram (ERG) recordings, that preventive, chronic treatment with saffron Repron[®] is able to reduce the neuroinflammation process and prevent the impairment of both cognitive and visual function. The improvement in behavioral and visual function is confirmed by the pattern of expression of neuroinflammation-related genes and related proteins where pre-treatment with Repron[®] saffron presents a positive modulation compared with that obtained in animals treated with LPS alone. These results hold for retinal tissue and partially in the brain, where it appears that the onset of damage was delayed. This trend underlines the critical role of the retina as a most sensitive portion of the central nervous system to LPS-induced damage and could be used as a "sensor" for the early detection of neurodegenerative diseases such as Alzheimer's.},
}

@article {pmid37765103,
year = {2023},
author = {Bhujbal, SP and Hah, JM},
title = {An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/ph16091295},
pmid = {37765103},
issn = {1424-8247},
support = {NRF-2020R1A6A1A03042854; HY-2023//This work was financially supported by a National Research Foundation of Korea grant, NRF-2020R1A6A1A03042854 (Center for Proteinopathy), and Hanyang University (HY-2023)./ ; },
abstract = {Owing to the dysregulation of protein kinase activity in various diseases such as cancer and autoimmune, cardiovascular, neurodegenerative, and inflammatory conditions, the protein kinase family has emerged as a crucial drug target in the 21st century. Notably, many kinases have been targeted to address cancer and neurodegenerative diseases using conventional ATP-mimicking kinase inhibitors. Likewise, irreversible covalent inhibitors have also been developed for different types of cancer. The application of covalent modification to target proteins has led to significant advancements in the treatment of cancer. However, while covalent drugs have significantly impacted medical treatment, their potential for neurodegenerative diseases remains largely unexplored. Neurodegenerative diseases present significant risks to brain function, leading to progressive deterioration in sensory, motor, and cognitive abilities. Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and multiple sclerosis (MS) are among the various examples of such disorders. Numerous research groups have already reported insights through reviews and research articles on FDA-approved covalent inhibitors, revealing their mechanisms and the specific covalent warheads that preferentially interact with particular amino acid residues in intricate detail. Hence, in this review, we aim to provide a concise summary of these critical topics. This summary endeavors to guide medicinal chemists in their quest to design covalent inhibitors for protein kinases, specifically targeting neurodegenerative diseases.},
}

@article {pmid37765003,
year = {2023},
author = {Angelova, VT and Georgiev, B and Pencheva, T and Pajeva, I and Rangelov, M and Todorova, N and Zheleva-Dimitrova, D and Kalcheva-Yovkova, E and Valkova, IV and Vassilev, N and Mihaylova, R and Stefanova, D and Petrov, B and Voynikov, Y and Tzankova, V},
title = {Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/ph16091194},
pmid = {37765003},
issn = {1424-8247},
support = {KP-06-N63/11, 14.12.2022//Bulgarian National Science Fund/ ; },
abstract = {Alzheimer's disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a-r) or sulfonyl hydrazone (5a-l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood-brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.},
}

@article {pmid37764355,
year = {2023},
author = {Sharma, P and Singh, M and Singh, V and Singh, TG and Singh, T and Ahmad, SF},
title = {Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {18},
pages = {},
doi = {10.3390/molecules28186579},
pmid = {37764355},
issn = {1420-3049},
abstract = {No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer's disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer's disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer's molecules.},
}

@article {pmid37764343,
year = {2023},
author = {Abo Mansour, HE and Elberri, AI and Ghoneim, ME and Samman, WA and Alhaddad, AA and Abdallah, MS and El-Berri, EI and Salem, MA and Mosalam, EM},
title = {The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {18},
pages = {},
doi = {10.3390/molecules28186566},
pmid = {37764343},
issn = {1420-3049},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder without effective treatment. Thymoquinone (TQ) has demonstrated potential in exhibiting anti-inflammatory, anti-cancer, and antioxidant characteristics. Despite TQ's neuroprotection effect, there is a scarcity of information regarding its application in AD research, and its molecular trajectories remain ambiguous. Thus, the objective of the current investigation was to examine the potential beneficial effects and underlying mechanisms of TQ in scopolamine (SCOP)-induced neuronal injury to mimic AD in vivo model.

METHODS: Thirty mice were divided into normal, SCOP, and TQ groups. The Y-maze and pole climbing tests were performed to measure memory and motor performance. Afterwards, histopathological and immunohistochemical examinations were carried out. Furthermore, peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway-related proteins and genes were detected with an emphasis on the role of miR-9.

RESULTS: TQ has the potential to ameliorate cognitive deficits observed in SCOP-induced AD-like model, as evidenced by the improvement in behavioral outcomes, histopathological changes, modulation of the expression pattern of PPAR-γ downstream targets with a significant decrease in the deposition of amyloid beta (Aβ).

CONCLUSIONS: TQ provided meaningful multilevel neuroprotection through its anti-inflammatory and its PPAR-γ agonist activity. Consequently, TQ may possess a potential beneficial role against AD development.},
}

@article {pmid37764150,
year = {2023},
author = {Li, Y and Wu, M and Kong, M and Sui, S and Wang, Q and He, Y and Gu, J},
title = {Impact of Donepezil Supplementation on Alzheimer's Disease-like Pathology and Gut Microbiome in APP/PS1 Mice.},
journal = {Microorganisms},
volume = {11},
number = {9},
pages = {},
doi = {10.3390/microorganisms11092306},
pmid = {37764150},
issn = {2076-2607},
support = {ZR2021LSW022//Nature Science Joint Foundation of Shandong Province/ ; 2021TSGC1279//Technological SMEs' innovation ability improvement project/ ; 202019191//Clinical Medical Science and Technology Innovation Program of Jinan/ ; QYPY2020NSFC0601//Cultivation Fund for the First Affiliated Hospital of Shandong First Medical University/ ; ZR2020MC004, ZR2021QH243//Nature Science Foundation of Shandong Province/ ; },
abstract = {Based on published information, the occurrence and development of Alzheimer's disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology.},
}

@article {pmid37763342,
year = {2023},
author = {Ozden, EM and Bingol, Z and Mutlu, M and Karagecili, H and Köksal, E and Goren, AC and Alwasel, SH and Gulcin, İ},
title = {Antioxidant, Antiglaucoma, Anticholinergic, and Antidiabetic Effects of Kiwifruit (Actinidia deliciosa) Oil: Metabolite Profile Analysis Using LC-HR/MS, GC/MS and GC-FID.},
journal = {Life (Basel, Switzerland)},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/life13091939},
pmid = {37763342},
issn = {2075-1729},
abstract = {Determining the antioxidant abilities and enzyme inhibition profiles of medicinally important plants and their oils is of great importance for a healthy life and the treatment of some common global diseases. Kiwifruit (Actinidia deliciosa) oil was examined and researched using several bioanalytical methods comprehensively for the first time in this research to determine its antioxidant, antiglaucoma, antidiabetic and anti-Alzheimer's capabilities. Additionally, the kiwifruit oil inhibitory effects on acetylcholinesterase (AChE), carbonic anhydrase II (CA II), and α-amylase, which are linked to a number of metabolic illnesses, were established. Furthermore, LC-HRMS analysis was used to assess the phenolic content of kiwifruit oil. It came to light that kiwifruit oil contained 26 different phenolic compounds. According to the LC-HRMS findings, kiwifruit oil is abundant in apigenin (74.24 mg/L oil), epigallocatechin (12.89 mg/L oil), caryophyllene oxide (12.89 mg/L oil), and luteolin (5.49 mg/L oil). In addition, GC-MS and GC-FID studies were used to ascertain the quantity and chemical composition of the essential oils contained in kiwifruit oil. Squalene (53.04%), linoleoyl chloride (20.28%), linoleic acid (2.67%), and palmitic acid (1.54%) were the most abundant compounds in kiwifruit oil. For radical scavenging activities of kiwifruit oil, 1,1-diphenyl-2-picryl-hydrazil (DPPH[•]) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS[•+]) radicals scavenging techniques were examined. These methods effectively demonstrated the potent radical scavenging properties of kiwifruit oil (IC50: 48.55 μg/mL for DPPH[•], and IC50: 77.00 μg/mL for ABTS[•+] scavenging). Also, for reducing capabilities, iron (Fe[3+]), copper (Cu[2+]), and Fe[3+]-2,4,6-tri(2-pyridyl)-S-triazine (TPTZ) reducing abilities were studied. Moreover, kiwifruit oil showed a considerable inhibition effect towards hCA II (IC50: 505.83 μg/mL), AChE (IC50: 12.80 μg/mL), and α-amylase (IC50: 421.02 μg/mL). The results revealed that the use of kiwifruit oil in a pharmaceutical procedure has very important effects due to its antioxidant, anti-Alzheimer, antidiabetic, and antiglaucoma effects.},
}

@article {pmid37762599,
year = {2023},
author = {Taneva, SG and Todinova, S and Andreeva, T},
title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814296},
pmid = {37762599},
issn = {1422-0067},
support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-Württemberg Ministry of Science, Research and Culture/ ; },
abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.},
}

@article {pmid37762479,
year = {2023},
author = {Olloquequi, J and Ettcheto, M and Cano, A and Fortuna, A and Bicker, J and Sánchez-Lopez, E and Paz, C and Ureña, J and Verdaguer, E and Auladell, C and Camins, A},
title = {Licochalcone A: A Potential Multitarget Drug for Alzheimer's Disease Treatment.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814177},
pmid = {37762479},
issn = {1422-0067},
abstract = {Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.},
}

@article {pmid37762420,
year = {2023},
author = {Vargas-Rodríguez, P and Cuenca-Martagón, A and Castillo-González, J and Serrano-Martínez, I and Luque, RM and Delgado, M and González-Rey, E},
title = {Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814117},
pmid = {37762420},
issn = {1422-0067},
support = {PID2020-119638RB-I00//Spanish Ministry of Science and Innovation/ ; },
abstract = {Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer's disease, Parkinson's disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts.},
}

@article {pmid37762386,
year = {2023},
author = {Go, MJ and Kim, JM and Lee, HL and Kim, TY and Joo, SG and Kim, JH and Lee, HS and Kim, DO and Heo, HJ},
title = {Anti-Amnesia-like Effect of Pinus densiflora Extract by Improving Apoptosis and Neuroinflammation on Trimethyltin-Induced ICR Mice.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814084},
pmid = {37762386},
issn = {1422-0067},
support = {821017-3//Ministry of Agriculture, Food and Rural Affairs/ ; },
abstract = {This study was conducted to investigate the anti-amnestic property of Korean red pine bark extract (KRPBE) on TMT-induced cognitive decline in ICR mice. As a result of looking at behavioral function, the consumption of KRPBE improved the spatial work ability, short-term learning, and memory ability by Y-maze, passive avoidance, and Morris water maze tests. KRPBE suppressed antioxidant system damage by assessing the SOD activity, reduced GSH content, and MDA levels in brain tissue. In addition, it had a protective effect on cholinergic and synaptic systems by regulating ACh levels, AChE activity, and protein expression levels of ChAT, AChE, SYP, and PSD-95. Also, the KRPBE ameliorated TMT-induced mitochondrial damage by regulating the ROS content, MMP, and ATP levels. Treatment with KRPBE suppressed Aβ accumulation and phosphorylation of tau and reduced the expression level of BAX/BCl-2 ratio and caspase 3, improving oxidative stress-induced apoptosis. Moreover, treatment with KRPBE improved cognitive dysfunction by regulating the neuro-inflammatory protein expression levels of p-JNK, p-Akt, p-IκB-α, COX-2, and IL-1β. Based on these results, the extract of Korean red pine bark, which is discarded as a byproduct of forestry, might be used as an eco-friendly material for functional foods or pharmaceuticals by having an anti-amnesia effect on cognitive impairment.},
}

@article {pmid37762366,
year = {2023},
author = {Kim, S and Jeon, J and Ganbat, D and Kim, T and Shin, K and Hong, S and Hong, J},
title = {Alteration of Neural Network and Hippocampal Slice Activation through Exosomes Derived from 5XFAD Nasal Lavage Fluid.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814064},
pmid = {37762366},
issn = {1422-0067},
support = {HI17C1711//Korea Health Industry Development Institute/Republic of Korea ; 2022R1A2C1093134//National Research Foundation of Korea/ ; 2018M3A9H1023323//National Research Foundation of Korea/ ; },
abstract = {Exosomes, key mediators of intercellular transmission of pathogenic proteins, such as amyloid-beta and tau, significantly influence the progression and exacerbation of Alzheimer's disease (AD) pathology. Present in a variety of biological fluids, including cerebrospinal fluid, blood, saliva, and nasal lavage fluid (NLF), exosomes underscore their potential as integral mediators of AD pathology. By serving as vehicles for disease-specific molecules, exosomes could unveil valuable insights into disease identification and progression. This study emphasizes the imperative to investigate the impacts of exosomes on neural networks to enhance our comprehension of intracerebral neuronal communication and its implications for neurological disorders like AD. After harvesting exosomes derived from NLF of 5XFAD mice, we utilized a high-density multielectrode array (HD-MEA) system, the novel technology enabling concurrent recordings from thousands of neurons in primary cortical neuron cultures and organotypic hippocampal slices. The ensuing results revealed a surge in neuronal firing rates and disoriented neural connectivity, reflecting the effects provoked by pathological amyloid-beta oligomer treatment. The local field potentials in the exosome-treated hippocampal brain slices also exhibited aberrant rhythmicity, along with an elevated level of current source density. While this research is an initial exploration, it highlights the potential of exosomes in modulating neural networks under AD conditions and endorses the HD-MEA as an efficacious tool for exosome studies.},
}

@article {pmid37762346,
year = {2023},
author = {Puranik, N and Yadav, D and Song, M},
title = {Advancements in the Application of Nanomedicine in Alzheimer's Disease: A Therapeutic Perspective.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241814044},
pmid = {37762346},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood-brain and blood-cerebrospinal fluid barriers are two barriers that protect the central nervous system, their presence has severely restricted the efficacy of many treatments that have been studied for AD diagnosis and/or therapy. The use of nanoparticles for the diagnosis and treatment of AD is the focus of an established and rapidly developing field of nanomedicine. Recent developments in nanomedicine have made it possible to effectively transport drugs to the brain. However, numerous obstacles remain to the successful use of nanomedicines in clinical settings for AD treatment. Furthermore, given the rapid advancement in nanomedicine therapeutics, better outcomes for patients with AD can be anticipated. This article provides an overview of recent developments in nanomedicine using different types of nanoparticles for the management and treatment of AD.},
}

@article {pmid37762276,
year = {2023},
author = {Rakovskaya, A and Erofeev, A and Vinokurov, E and Pchitskaya, E and Dahl, R and Bezprozvanny, I},
title = {Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer's Disease Mouse Model.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813973},
pmid = {37762276},
issn = {1422-0067},
support = {R01AG071310//National Institute of Health/ ; R42AG062001//National Institute of Health/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca[2+]) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabilize Ca[2+] neuronal signaling can act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the sarco/endoplasmic reticulum Ca[2+] ATPase (SERCA) pump might act as such Ca[2+]-stabilizing agents and exhibit neuroprotective properties. In the present study, we evaluated effects of a set of novel SERCA PAM agents on the rate of Ca[2+] extraction from the cytoplasm of the HEK293T cell line, on morphometric parameters of dendritic spines of primary hippocampal neurons in normal conditions and in conditions of amyloid toxicity, and on long-term potentiation in slices derived from 5xFAD transgenic mice modeling AD. Several SERCA PAM compounds demonstrated neuroprotective properties, and the compound NDC-9009 showed the best results. The findings in this study support the hypothesis that the SERCA pump is a potential therapeutic target for AD treatment and that NDC-9009 is a promising lead molecule to be used in the development of disease-modifying agents for AD.},
}

@article {pmid37762203,
year = {2023},
author = {Buccellato, FR and D'Anca, M and Tartaglia, GM and Del Fabbro, M and Scarpini, E and Galimberti, D},
title = {Treatment of Alzheimer's Disease: Beyond Symptomatic Therapies.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813900},
pmid = {37762203},
issn = {1422-0067},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.},
}

@article {pmid37762089,
year = {2023},
author = {Mousa, WK and Mousa, S and Ghemrawi, R and Obaid, D and Sarfraz, M and Chehadeh, F and Husband, S},
title = {Probiotics Modulate Host Immune Response and Interact with the Gut Microbiota: Shaping Their Composition and Mediating Antibiotic Resistance.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813783},
pmid = {37762089},
issn = {1422-0067},
support = {Ph2022-3-100//Al Ain University of Science and Technology/ ; },
abstract = {The consortium of microbes inhabiting the human body, together with their encoded genes and secreted metabolites, is referred to as the "human microbiome." Several studies have established a link between the composition of the microbiome and its impact on human health. This impact spans local gastrointestinal inflammation to systemic autoimmune disorders and neurodegenerative diseases such as Alzheimer's and Autism. Some of these links have been validated by rigorous experiments that identify specific strains as mediators or drivers of a particular condition. Consequently, the development of probiotics to compensate for a missing beneficial microbe(s) has advanced and become popular, especially in the treatment of irritable bowel diseases and to restore disrupted gut flora after antibiotic administration. The widespread use of probiotics is often advocated as a natural ecological therapy. However, this perception is not always accurate, as there is a potential for unexpected interactions when administering live microbial cultures. Here, we designed this research to explore the intricate interactions among probiotics, the host, and microbes through a series of experiments. Our objectives included assessing their immunomodulatory effects, response to oral medications, impact on microbial population dynamics, and mediation of antibiotic resistance. To achieve these goals, we employed diverse experimental protocols, including cell-based enzyme -linked immunosorbent assay (ELISA), antibiotic susceptibility testing, antimicrobial activity assays, computational prediction of probiotic genes responsible for antibiotic resistance, polymerase chain reaction (PCR)-based validation of predicted genes, and survival assays of probiotics in the presence of selected oral medications. Our findings highlight that more than half of the tested probiotics trigger an inflammatory response in the Caco-2 cell line, are influenced by oral medications, exhibit antibacterial activity, and possess genes encoding antimicrobial resistance. These results underscore the necessity for a reevaluation of probiotic usage and emphasize the importance of establishing regulations to govern probiotic testing, approval, and administration.},
}

@article {pmid37762050,
year = {2023},
author = {Arastoo, M and Mazanetz, MP and Miller, S and Shiells, H and Hull, C and Robinson, K and Storey, JMD and Harrington, CR and Wischik, CM},
title = {Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813747},
pmid = {37762050},
issn = {1422-0067},
abstract = {Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO2) and lower respiratory rates in patients with severe COVID-19. We have developed a stable form of reduced methylthionine (hydromethylthionine-mesylate, HMTM) having a benign safety profile in two Phase 3 trials in Alzheimer's disease. The aim of this prospective study was to determine the effects of oral HMTM on SpO2 and methaemoglobin (metHb) levels in a cohort of patients with mild hypoxaemia not due to COVID-19. Eighteen participants randomised to a single dose of 4, 75, 100 or 125 mg doses of HMTM had SpO2 levels below 94% at baseline. Patients were routinely monitored by pulse oximetry after 4 h, and after 2 and 6 weeks of twice daily dosing. Significant ~3% increases in SpO2 occurred within 4 h and were sustained over 2 and 6 weeks with no dose differences. There were small dose-dependent increases (0.060-0.162%) in metHb levels over 2 to 6 weeks. Minimum-energy computational chemistry revealed that HMT can bind within 2.10 Å of heme iron by donating a pair of electrons from the central nitrogen of HMT to d orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2 without reducing metHb by acting as a strong displaceable field ligand for heme iron. We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia.},
}

@article {pmid37761746,
year = {2023},
author = {Sánchez-Rodríguez, MT and Pinzón-Bernal, MY and Jiménez-Antona, C and Laguarta-Val, S and Sánchez-Herrera-Baeza, P and Fernández-González, P and Cano-de-la-Cuerda, R},
title = {Designing an Informative App for Neurorehabilitation: A Feasibility and Satisfaction Study by Physiotherapists.},
journal = {Healthcare (Basel, Switzerland)},
volume = {11},
number = {18},
pages = {},
doi = {10.3390/healthcare11182549},
pmid = {37761746},
issn = {2227-9032},
abstract = {BACKGROUND: New technologies have gained popularity, especially the use of mobile phone applications, in neurorehabilitation. The aim of this paper was (1) to develop a free mobile application (NeurorehAPP) that provides information about and helps to select the appropriate mobile application related to a list of neurological disorders (cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, stroke, cerebral palsy, muscular dystrophy, spina bifida, and facial paralysis), based on different objectives such as healthy habits, information, assessment, and treatment; and (2) to assess the feasibility, acceptability, and degree of satisfaction by physiotherapists after using NeurorehAPP for a minimum of three months.

METHODS: A free application was created to work with the Android[®] operating system. The degree of satisfaction and acceptance with the application was assessed with an adaptation of the Customer Satisfaction Questionnaire through a survey via email applied to physiotherapists from hospitals and neurological rehabilitation centers in Spain after using the application.

RESULTS: NeurorehAPP includes a total of 131 apps. A total of 121 physiotherapists completed a satisfaction survey. The total sample showed 85.41% satisfaction with the service provided by the app and 86.41% overall satisfaction with NeurorehAPP.

CONCLUSIONS: NeurorehAPP is a free, intuitive, and friendly app used with the Android[®] operating system that allows the selection of the most appropriate app according to the type of user, neurological disorder, objective, and FDA criteria. Physiotherapists showed a high degree of satisfaction and acceptance with NeurorehAPP.},
}

@article {pmid37761028,
year = {2023},
author = {Sivamaruthi, BS and Raghani, N and Chorawala, M and Bhattacharya, S and Prajapati, BG and Elossaily, GM and Chaiyasut, C},
title = {NF-κB Pathway and Its Inhibitors: A Promising Frontier in the Management of Alzheimer's Disease.},
journal = {Biomedicines},
volume = {11},
number = {9},
pages = {},
doi = {10.3390/biomedicines11092587},
pmid = {37761028},
issn = {2227-9059},
abstract = {The nuclear factor kappa B (NF-κB) pathway has emerged as a pivotal player in the pathogenesis of various diseases, including neurodegenerative illnesses like Alzheimer's disease (AD). The involvement of the NF-κB pathway in immune system responses, inflammation, oxidative stress, and neuronal survival highlights its significance in AD progression. We discuss the advantages of NF-κB pathway inhibition, including the potential to mitigate neuroinflammation, modulate amyloid beta (Aβ) production, and promote neuronal survival. However, we also acknowledge the limitations and challenges associated with this approach. Balancing the fine line between dampening inflammation and preserving physiological immune responses is critical to avoid unintended consequences. This review combines current knowledge on the NF-κB pathway's intricate involvement in AD pathogenesis, emphasizing its potential as a therapeutic target. By evaluating both advantages and limitations, we provide a holistic view of the feasibility and challenges of NF-κB pathway modulation in AD treatment. As the quest for effective AD therapies continues, an in-depth understanding of the NF-κB pathway's multifaceted roles will guide the development of targeted interventions with the potential to improve AD management.},
}

@article {pmid37760893,
year = {2023},
author = {Jabeen, K and Rehman, K and Akash, MSH and Nadeem, A and Mir, TM},
title = {Neuroprotective and Cardiometabolic Role of Vitamin E: Alleviating Neuroinflammation and Metabolic Disturbance Induced by AlCl3 in Rat Models.},
journal = {Biomedicines},
volume = {11},
number = {9},
pages = {},
doi = {10.3390/biomedicines11092453},
pmid = {37760893},
issn = {2227-9059},
support = {(RSP2023R124)//Researchers Supporting Project Number (RSP2023R124), King Saud University, Riyadh, Saudi Arabia./ ; },
abstract = {Cardiovascular diseases (CVDs) and neurodegenerative disorders, such as diabetes mellitus and Alzheimer's disease, share a common pathophysiological link involving insulin resistance (IR), inflammation, and hypertension. Aluminium chloride (AlCl3), a known neurotoxicant, has been associated with neurodegeneration, cognitive impairment, and various organ dysfunctions due to the production of reactive oxygen species (ROS) and oxidative stress. In this study, we aimed to investigate the potential protective effects of metformin and vitamin E against AlCl3-induced neuroinflammation and cardiometabolic disturbances in rat models. Rats were divided into five groups: a normal control group, an AlCl3-treated diseased group without any treatment, and three groups exposed to AlCl3 and subsequently administered with metformin (100 mg/kg/day) alone, vitamin E (150 mg/kg/day) orally alone, or a combination of metformin (100 mg/kg/day) and vitamin E (150 mg/kg/day) for 45 days. We analyzed serum biomarkers and histopathological changes in brain, heart, and pancreatic tissues using H&E and Masson's trichrome staining and immunohistochemistry (IHC). Electrocardiogram (ECG) patterns were observed for all groups. The AlCl3-treated group showed elevated levels of inflammatory biomarkers, MDA, and disturbances in glycemic and lipid profiles, along with reduced insulin levels. However, treatment with the combination of metformin and vitamin E resulted in significantly reduced glucose, cholesterol, LDL, and TG levels, accompanied by increased insulin and HDL levels compared to the individual treatment groups. Histopathological analyses revealed that combination therapy preserved neuronal structures, muscle cell nuclei, and normal morphology in the brain, heart, and pancreatic tissues. IHC demonstrated reduced amyloid plaques and neurofibrillary tangles in the combination-treated group compared to the AlCl3-treated group. Moreover, the combination group showed a normal ECG pattern, contrasting the altered pattern observed in the AlCl3-treated group. Overall, our findings suggest that metformin and vitamin E, in combination, possess neuroprotective and cardiometabolic effects, alleviating AlCl3-induced neuroinflammation and metabolic disturbances.},
}

@article {pmid37760774,
year = {2023},
author = {Sousa, T and Moreira, PI and Cardoso, S},
title = {Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease.},
journal = {Biomedicines},
volume = {11},
number = {9},
pages = {},
doi = {10.3390/biomedicines11092331},
pmid = {37760774},
issn = {2227-9059},
support = {UIDP/04539/2020//Fundação para a Ciência e Tecnologia/ ; LA/P/0058/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/04539/2020//Fundação para a Ciência e Tecnologia/ ; },
abstract = {Alzheimer's disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD's cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria's health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.},
}

@article {pmid37760195,
year = {2023},
author = {Ahn, K and Cho, M and Kim, SW and Lee, KE and Song, Y and Yoo, S and Jeon, SY and Kim, JL and Yoon, DH and Kong, HJ},
title = {Deep Learning of Speech Data for Early Detection of Alzheimer's Disease in the Elderly.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {10},
number = {9},
pages = {},
doi = {10.3390/bioengineering10091093},
pmid = {37760195},
issn = {2306-5354},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, which makes the lives of patients and their families difficult for various reasons. Therefore, early detection of AD is crucial to alleviating the symptoms through medication and treatment.

OBJECTIVE: Given that AD strongly induces language disorders, this study aims to detect AD rapidly by analyzing the language characteristics.

MATERIALS AND METHODS: The mini-mental state examination for dementia screening (MMSE-DS), which is most commonly used in South Korean public health centers, is used to obtain negative answers based on the questionnaire. Among the acquired voices, significant questionnaires and answers are selected and converted into mel-frequency cepstral coefficient (MFCC)-based spectrogram images. After accumulating the significant answers, validated data augmentation was achieved using the Densenet121 model. Five deep learning models, Inception v3, VGG19, Xception, Resnet50, and Densenet121, were used to train and confirm the results.

RESULTS: Considering the amount of data, the results of the five-fold cross-validation are more significant than those of the hold-out method. Densenet121 exhibits a sensitivity of 0.9550, a specificity of 0.8333, and an accuracy of 0.9000 in a five-fold cross-validation to separate AD patients from the control group.

CONCLUSIONS: The potential for remote health care can be increased by simplifying the AD screening process. Furthermore, by facilitating remote health care, the proposed method can enhance the accessibility of AD screening and increase the rate of early AD detection.},
}

@article {pmid37759933,
year = {2023},
author = {Millet, B and Mouchabac, S and Robert, G and Maatoug, R and Dondaine, T and Ferreri, F and Bourla, A},
title = {Transcranial Magnetic Stimulation (rTMS) on the Precuneus in Alzheimer's Disease: A Literature Review.},
journal = {Brain sciences},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/brainsci13091332},
pmid = {37759933},
issn = {2076-3425},
abstract = {The current literature review aimed to evaluate the effectiveness of rTMS on the precuneus as a potential treatment for Alzheimer's disease (AD). Although the number of studies specifically targeting the precuneus is limited, the results from this review suggest the potential benefits of this approach. Future studies should focus on exploring the long-term effects of rTMS on the precuneus in Alzheimer's disease patients, as well as determining the optimal stimulation parameters and protocols for this population. Additionally, investigating the effects of rTMS on the precuneus in combination with other brain regions implicated in AD may provide valuable insights into the development of effective treatment for this debilitating neurodegenerative disorder.},
}

@article {pmid37759788,
year = {2023},
author = {Voicu, V and Brehar, FM and Toader, C and Covache-Busuioc, RA and Corlatescu, AD and Bordeianu, A and Costin, HP and Bratu, BG and Glavan, LA and Ciurea, AV},
title = {Cannabinoids in Medicine: A Multifaceted Exploration of Types, Therapeutic Applications, and Emerging Opportunities in Neurodegenerative Diseases and Cancer Therapy.},
journal = {Biomolecules},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/biom13091388},
pmid = {37759788},
issn = {2218-273X},
abstract = {In this review article, we embark on a thorough exploration of cannabinoids, compounds that have garnered considerable attention for their potential therapeutic applications. Initially, this article delves into the fundamental background of cannabinoids, emphasizing the role of endogenous cannabinoids in the human body and outlining their significance in studying neurodegenerative diseases and cancer. Building on this foundation, this article categorizes cannabinoids into three main types: phytocannabinoids (plant-derived cannabinoids), endocannabinoids (naturally occurring in the body), and synthetic cannabinoids (laboratory-produced cannabinoids). The intricate mechanisms through which these compounds interact with cannabinoid receptors and signaling pathways are elucidated. A comprehensive overview of cannabinoid pharmacology follows, highlighting their absorption, distribution, metabolism, and excretion, as well as their pharmacokinetic and pharmacodynamic properties. Special emphasis is placed on the role of cannabinoids in neurodegenerative diseases, showcasing their potential benefits in conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. The potential antitumor properties of cannabinoids are also investigated, exploring their potential therapeutic applications in cancer treatment and the mechanisms underlying their anticancer effects. Clinical aspects are thoroughly discussed, from the viability of cannabinoids as therapeutic agents to current clinical trials, safety considerations, and the adverse effects observed. This review culminates in a discussion of promising future research avenues and the broader implications for cannabinoid-based therapies, concluding with a reflection on the immense potential of cannabinoids in modern medicine.},
}

@article {pmid37759724,
year = {2023},
author = {Dennison, J and Mendez, A and Szeto, A and Lohse, I and Wahlestedt, C and Volmar, CH},
title = {Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse.},
journal = {Biomolecules},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/biom13091324},
pmid = {37759724},
issn = {2218-273X},
support = {R56AG061911/AG/NIA NIH HHS/United States ; R01AG079373/AG/NIA NIH HHS/United States ; },
abstract = {Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer's disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results. This is remarkable because there is rising evidence that epigenetic compounds intrinsically affect males and females differently. This manuscript explores the sexual dimorphism observed after chronic, low-dose administration of a clinically relevant histone deacetylase inhibitor, chidamide (Tucidinostat), in the 3xTg-AD mouse model. We found that chidamide treatment significantly improves glucose tolerance and increases expression of glucose transporters in the brain of males. We also report a decrease in total tau in chidamide-treated mice. Differentially expressed genes in chidamide-treated mice were much greater in males than females. Genes involved in the neuroinflammatory pathway and amyloid processing pathway were mostly upregulated in chidamide-treated males while downregulated in chidamide-treated females. This work highlights the need for drug discovery projects to consider sex as a biological variable to facilitate translation.},
}

@article {pmid37759689,
year = {2023},
author = {Ponce-Lopez, T and González Álvarez Tostado, JA and Dias, F and Montiel Maltez, KH},
title = {Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats.},
journal = {Biomolecules},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/biom13091289},
pmid = {37759689},
issn = {2218-273X},
support = {ID-201855//Investigaciones y Estudios Superiores S.C./ ; },
abstract = {N-nitrosodiethylamine (NDEA) is a potential carcinogen known to cause liver tumors and chronic inflammation, diabetes, cognitive problems, and signs like Alzheimer's disease (AD) in animals. This compound is classified as probably carcinogenic to humans. Usual sources of exposure include food, beer, tobacco, personal care products, water, and medications. AD is characterized by cognitive decline, amyloid-β (Aβ) deposit, tau hyperphosphorylation, and cell loss. This is accompanied by neuroinflammation, which involves release of microglial cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β), by nuclear factor kappa B (NF-κB) upregulation; each are linked to AD progression. Weak PI3K/Akt insulin-signaling inhibits IRS-1 phosphorylation, activates GSK3β and promotes tau hyperphosphorylation. Metformin, an antihyperglycemic agent, has potent anti-inflammatory efficacy. It reduces proinflammatory cytokines such as IL-6, IL-1β, and TNF-α via NF-κB inhibition. Metformin also reduces reactive oxidative species (ROS) and modulates cognitive disorders reported due to brain insulin resistance links. Our study examined how NDEA affects spatial memory in Wistar rats. We found that all NDEA doses tested impaired memory. The 80 µg/kg dose of NDEA increased levels of Aβ1-42, TNF-α, and IL-6 in the hippocampus, which correlated with memory loss. Nonetheless, treatment with 100 mg/kg of metformin attenuated the levels of pro-inflammatory cytokines and Aβ1-42, and enhanced memory. It suggests that metformin may protect against NDEA-triggered memory issues and brain inflammation.},
}

@article {pmid37759477,
year = {2023},
author = {Morello, G and Guarnaccia, M and La Cognata, V and Latina, V and Calissano, P and Amadoro, G and Cavallaro, S},
title = {Transcriptomic Analysis in the Hippocampus and Retina of Tg2576 AD Mice Reveals Defective Mitochondrial Oxidative Phosphorylation and Recovery by Tau 12A12mAb Treatment.},
journal = {Cells},
volume = {12},
number = {18},
pages = {},
doi = {10.3390/cells12182254},
pmid = {37759477},
issn = {2073-4409},
support = {DSB.AD007.304//National Research Council/ ; FOE D.M865/2019//National Research Council/ ; T0002E0001 G04014_13_04_2021//Regione Lazio, POR FESR Lazio 2014-2020/ ; RF-2021-12374301//Ministry of Health/ ; },
abstract = {Increasing evidence implicates decreased energy metabolism and mitochondrial dysfunctions among the earliest pathogenic events of Alzheimer's disease (AD). However, the molecular mechanisms underlying bioenergetic dysfunctions in AD remain, to date, largely unknown. In this work, we analyzed transcriptomic changes occurring in the hippocampus and retina of a Tg2576 AD mouse model and wild-type controls, evaluating their functional implications by gene set enrichment analysis. The results revealed that oxidative phosphorylation and mitochondrial-related pathways are significantly down-regulated in both tissues of Tg2576 mice, supporting the role of these processes in the pathogenesis of AD. In addition, we also analyzed transcriptomic changes occurring in Tg2576 mice treated with the 12A12 monoclonal antibody that neutralizes an AD-relevant tau-derived neurotoxic peptide in vivo. Our analysis showed that the mitochondrial alterations observed in AD mice were significantly reverted by treatment with 12A12mAb, supporting bioenergetic pathways as key mediators of its in vivo neuroprotective and anti-amyloidogenic effects. This study provides, for the first time, a comprehensive characterization of molecular events underlying the disrupted mitochondrial bioenergetics in AD pathology, laying the foundation for the future development of diagnostic and therapeutic tools.},
}

@article {pmid37759382,
year = {2023},
author = {Wang, X and Zhou, R and Sun, X and Li, J and Wang, J and Yue, W and Wang, L and Liu, H and Shi, Y and Zhang, D},
title = {Preferential Regulation of Γ-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2303411},
doi = {10.1002/advs.202303411},
pmid = {37759382},
issn = {2198-3844},
support = {2022ZD0211800//STI2030-Major Projects/ ; 2021B-01-01//Changping laboratory/ ; 2020YFA0509300//National Key Research and Development Program of China/ ; //Ministry of Science and Technology of China/ ; 81920108015//National Natural Science Foundation of China/ ; 2020C04001//Key R&D Program of Zhejiang Province/ ; },
abstract = {A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β-amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of γ-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ-secretase structure and specifically accelerates γ-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ-secretase activity and the pathogenesis of AD.},
}

@article {pmid37758932,
year = {2023},
author = {Huang, M and Sui, R and Zhang, L and Zhu, Y and Yuan, X and Jiang, H and Mao, X},
title = {Rosavin thwarts amyloid-β-induced macromolecular damages and neurotoxicity, exhibiting anti-Alzheimer's disease activity in Wister rat model.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {37758932},
issn = {1568-5608},
support = {2019-ZD-0802//Liaoning Provincial Natural Science Foundation Guidance Plan Project/ ; 10160058//the Innovation Training Program of Jinzhou Medical University/ ; },
abstract = {Lately, interest surrounding the utilization of plant-derived compounds as a viable beneficial approach for treating Alzheimer's disease (AD) has significantly increased. This study aimed to assess the defensive properties of rosavin against Alzheimer's disease induced by amyloid-β, utilizing experimental models. We found that rosavin exhibited anti-aggregation and disaggregation properties, suggesting its potential to prevent the gathering of Aβ-aggregates. In vitro experiments revealed that rosavin effectively mitigated the neurotoxicity induced by Aβ in Neuro-2a cells, showcasing its protective potential. Rosavin significantly improved the Aβ-induced cognitive deficits in Wistar rats, particularly in spatial memory. Which the pathophysiology of AD includes oxidative damage, which negatively impacts biological macromolecules. Triggers the apoptotic process, causing macromolecular destruction. Interestingly, rosavin attenuated Aβ-induced macromolecular damages, thereby preserving neuronal integrity. Furthermore, the activation of antioxidative defense enzymes by rosavin inhibited oxidative damage. The positive outcomes associated with rosavin were primarily attributed to its capacity to enhance acetylcholine-mediated effects. Finally, rosavin has the potential to alleviate Aβ-induced neurotoxicity and macromolecular damages, ultimately resulting in enhanced memorial and reasoning function in Wistar rats, offering promising prospects for the treatment of AD.},
}

@article {pmid37758186,
year = {2023},
author = {Ehrenzweig, J and Hunter, RP},
title = {Canine cognitive decline and Alzheimer disease: clinical insights to solve a shared one-health problem.},
journal = {Journal of the American Veterinary Medical Association},
volume = {},
number = {},
pages = {1-8},
doi = {10.2460/javma.23.02.0095},
pmid = {37758186},
issn = {1943-569X},
abstract = {Alzheimer disease (AD) is the leading cause of dementia among older adults. Current AD treatment options are limited, and the absence of appropriate research animals has significantly hindered the development of new AD therapies. Canine cognitive decline (CCD) is a major determinant of morbidity in older animals, with alterations in blood biomarkers, neuropathology, physiology, and behavior comparable to those seen in humans diagnosed with dementia and AD. The one-health goal of achieving optimal health is supported by academics, researchers, and governments. Veterinarians' ability to identify patients in the early stages of CCD is crucial to the successful implementation of interventions that can improve the quality of life of affected dogs. Timely identification of CCD also opens opportunities for innovative interdisciplinary research that will contribute to a better understanding of the underlying mechanisms, early detection, and effective treatments for AD, ultimately benefiting human health as well. Until now, veterinary practitioners have played limited roles as interdisciplinary leaders in the One Health initiative to combat disease. The authors discuss how client-owned animals with spontaneous, naturally occurring CCD can play a significant role as disease-relevant surrogates for translational AD research. The proposed Dogs Overcoming Geriatric Memory and Aging (DOGMA) Study to be conducted in veterinary practices will analyze the relationship between blood biomarkers and biometric behavior in mature and older dogs, with the aim of establishing benchmark CCD data. The DOGMA Study is addressed in the companion Currents in One Health by Hunter et al, AJVR, November 2023.},
}

@article {pmid37755583,
year = {2023},
author = {Kim, SK and Lee, GY and Kim, SK and Kwon, YJ and Seo, EB and Lee, H and Lee, SH and Kim, SJ and Lee, S and Ye, SK},
title = {Protective Effects of Repetitive Transcranial Magnetic Stimulation Against Streptozotocin-Induced Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {37755583},
issn = {1559-1182},
support = {NRF-2018R1A5A2025964//National Research Foundation of Korea (NRF) funded by the Korean government/ ; NRF-2022R1A2C1011914//National Research Foundation of Korea (NRF) funded by the Korean government/ ; 2022RIS-005//the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE)/ ; 2020195A00-2122-BA01//the R&D Program for Forest Science Technology of the Korea Forest Service (Korea Forestry Promotion Institute)/ ; Project No. PJ01589402//Philippine Council for Agriculture, Aquatic and Natural Resources Research and Development/ ; Project No. PJ016020012021//Philippine Council for Agriculture, Aquatic and Natural Resources Research and Development/ ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation under investigation for treatment of a wide range of neurological disorders. In particular, the therapeutic application of rTMS for neurodegenerative diseases such as Alzheimer's disease (AD) is attracting attention. However, the mechanisms underlying the therapeutic efficacy of rTMS have not yet been elucidated, and few studies have systematically analyzed the stimulation parameters. In this study, we found that treatment with rTMS contributed to restoration of memory deficits by activating genes involved in synaptic plasticity and long-term memory. We evaluated changes in several intracellular signaling pathways in response to rTMS stimulation; rTMS treatment activated STAT, MAPK, Akt/p70S6K, and CREB signaling. We also systematically investigated the influence of rTMS parameters. We found an effective range of applications for rTMS and determined the optimal combination to achieve the highest efficiency. Moreover, application of rTMS inhibited the increase in cell death induced by hydrogen peroxide. These results suggest that rTMS treatment exerts a neuroprotective effect on cellular damage induced by oxidative stress, which plays an important role in the pathogenesis of neurological disorders. rTMS treatment attenuated streptozotocin (STZ)-mediated cell death and AD-like pathology in neuronal cells. In an animal model of sporadic AD caused by intracerebroventricular STZ injection, rTMS application improved cognitive decline and showed neuroprotective effects on hippocampal histology. Overall, this study will help in the design of stimulation protocols for rTMS application and presents a novel mechanism that may explain the therapeutic effects of rTMS in neurodegenerative diseases, including AD.},
}

@article {pmid37754272,
year = {2023},
author = {Murai, T and Matsuda, S},
title = {Integrated Multimodal Omics and Dietary Approaches for the Management of Neurodegeneration.},
journal = {Epigenomes},
volume = {7},
number = {3},
pages = {},
doi = {10.3390/epigenomes7030020},
pmid = {37754272},
issn = {2075-4655},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are caused by a combination of multiple events that damage neuronal function. A well-characterized biomarker of neurodegeneration is the accumulation of proteinaceous aggregates in the brain. However, the gradually worsening symptoms of neurodegenerative diseases are unlikely to be solely due to the result of a mutation in a single gene, but rather a multi-step process involving epigenetic changes. Recently, it has been suggested that a fraction of epigenetic alternations may be correlated to neurodegeneration in the brain. Unlike DNA mutations, epigenetic alterations are reversible, and therefore raise the possibilities for therapeutic intervention, including dietary modifications. Additionally, reactive oxygen species may contribute to the pathogenesis of Alzheimer's disease and Parkinson's disease through epigenetic alternation. Given that the antioxidant properties of plant-derived phytochemicals are likely to exhibit pleiotropic effects against ROS-mediated epigenetic alternation, dietary intervention may be promising for the management of neurodegeneration in these diseases. In this review, the state-of-the-art applications using single-cell multimodal omics approaches, including epigenetics, and dietary approaches for the identification of novel biomarkers and therapeutic approaches for the treatment of neurodegenerative diseases are discussed.},
}

@article {pmid37754114,
year = {2023},
author = {Gao, F and Li, F and Wang, J and Yu, H and Li, X and Chen, H and Wang, J and Qin, D and Li, Y and Liu, S and Zhang, X and Wang, ZH},
title = {SERS-Based Optical Nanobiosensors for the Detection of Alzheimer's Disease.},
journal = {Biosensors},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/bios13090880},
pmid = {37754114},
issn = {2079-6374},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.},
}

@article {pmid37754093,
year = {2023},
author = {Huang, L and Yang, J and Liang, Z and Liang, R and Luo, H and Sun, Z and Han, D and Niu, L},
title = {Ternary Heterojunction Graphitic Carbon Nitride/Cupric Sulfide/Titanium Dioxide Photoelectrochemical Sensor for Sesamol Quantification and Antioxidant Synergism.},
journal = {Biosensors},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/bios13090859},
pmid = {37754093},
issn = {2079-6374},
support = {the National Key R&D Program of China//the National Key R&D Program of China/ ; 22172040 and 21974031//the National Natural Science Foundation of China/ ; 220605940231526//the University-Industry Collaborative Education Program of Ministry of Education of China/ ; 2023B1515040004//the Guangdong Basic and Applied Basic Research Foundation/ ; 2021A1515010180 and 2019B010933001//the Department of Science and Techniques of Guangdong Province/ ; GZQC20-PZ11-FD084//the Department of Guangdong Provincial Public Security/ ; 202102010449//the Science and Technology Projects in Guangzhou/ ; 2022A156//the Department of Science & Technology of Guangdong Province/ ; 202102010449//the Guangzhou Municipal Science and Technology Bureau/ ; 202235344//the Tertiary Education Scientific Research Project of Guangzhou Municipal Education Bureau/ ; 2022M720867//the China Postdoctoral Science Foundation/ ; },
abstract = {Sesamol (SM) is a potent natural antioxidant that can quench free radicals and modulate the cholinergic system in the brain, thereby ameliorating memory and cognitive impairment in Alzheimer's disease patients. Moreover, the total antioxidant capacity can be amplified by synergistic interactions between different antioxidants. Here, we constructed a ternary heterojunction graphitic carbon nitride/cupric sulfide/titanium dioxide (g-C3N4/CuS/TiO2) photoelectrochemical (PEC) sensor for the quantification of SM and its synergistic interactions with other antioxidants. Crucially, the Schottky barrier in ternary semiconductors considerably enhances electron transfer. The PEC sensor showed a wide linear range for SM detection, ranging from 2 to 1277 μmol L[-1], and had a limit of detection of 1.8 μmol L[-1]. Remarkably, this sensing platform could evaluate the synergism between SM and five typical lipid-soluble antioxidants: tert-butyl hydroquinone, vitamin E, butyl hydroxyanisole, propyl gallate, and butylated hydroxytoluene. Owing to its low redox potential, SM could reduce antioxidant radicals and promote their regeneration, which increased the overall antioxidant performance. The g-C3N4/CuS/TiO2 PEC sensor exhibited high sensitivity, satisfactory selectivity, and stability, and was successfully applied for SM determination in both soybean and peanut oils. The findings of this study provide guidance for the development of nutritional foods, nutrition analysis, and the treatment of diseases caused by free radicals.},
}

@article {pmid37753585,
year = {2023},
author = {Golmohammadi, M and Mahmoudian, M and Hasan, EK and Alshahrani, SH and Romero-Parra, RM and Malviya, J and Hjazi, A and Najm, MAA and Almulla, AF and Zamanian, MY and Kadkhodaei, M and Mousavi, N},
title = {Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review.},
journal = {Fundamental & clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/fcp.12955},
pmid = {37753585},
issn = {1472-8206},
abstract = {BACKGROUND: Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases.

OBJECTIVE: The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms.

METHODS: The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles.

RESULTS: Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2.

CONCLUSION: In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.},
}

@article {pmid37753266,
year = {2023},
author = {He, C and Li, Z and Yang, M and Yu, W and Luo, R and Zhou, J and He, J and Chen, Q and Song, Z and Cheng, S},
title = {Non-Coding RNA in Microglia Activation and Neuroinflammation in Alzheimer's Disease.},
journal = {Journal of inflammation research},
volume = {16},
number = {},
pages = {4165-4211},
pmid = {37753266},
issn = {1178-7031},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathophysiological features. Amyloid plaques resulting from extracellular amyloid deposition and neurofibrillary tangles formed by intracellular hyperphosphorylated tau accumulation serve as primary neuropathological criteria for AD diagnosis. The activation of microglia has been closely associated with these pathological manifestations. Non-coding RNA (ncRNA), a versatile molecule involved in various cellular functions such as genetic information storage and transport, as well as catalysis of biochemical reactions, plays a crucial role in microglial activation. This review aims to investigate the regulatory role of ncRNAs in protein expression by directly targeting genes, proteins, and interactions. Furthermore, it explores the ability of ncRNAs to modulate inflammatory pathways, influence the expression of inflammatory factors, and regulate microglia activation, all of which contribute to neuroinflammation and AD. However, there are still significant controversies surrounding microglial activation and polarization. The categorization into M1 and M2 phenotypes may oversimplify the intricate and multifaceted regulatory processes in microglial response to neuroinflammation. Limited research has been conducted on the role of ncRNAs in regulating microglial activation and inducing distinct polarization states in the context of neuroinflammation. Moreover, the regulatory mechanisms through which ncRNAs govern microglial function continue to be refined. The current understanding of ncRNA regulatory pathways involved in microglial activation remains incomplete and may be influenced by spatial, temporal, and tissue-specific factors. Therefore, further in-depth investigations are warranted. In conclusion, there are ongoing debates and uncertainties regarding the activation and polarization of microglial cells, particularly concerning the categorization into M1 and M2 phenotypes. The study of ncRNA regulation in microglial activation and polarization, as well as its mechanisms, is still in its early stages and requires further investigation. However, this review offers new insights and opportunities for therapeutic approaches in AD. The development of ncRNA-based drugs may hold promise as a new direction in AD treatment.},
}

@article {pmid37752907,
year = {2023},
author = {Fischer, B and Van Hulle, CA and Langhough, R and Norton, D and Zuelsdorff, M and Gooding, DC and Wyman, MF and Johnson, A and Lambrou, N and James, T and Bouges, S and Carter, FP and Salazar, H and Kirmess, K and Holubasch, M and Meyer, M and Venkatesh, V and West, T and Verghese, P and Yarasheski, K and Carlsson, CM and Johnson, SC and Asthana, S and Gleason, CE},
title = {Plasma Aβ42/40 and cognitive variability are associated with cognitive function in Black Americans: Findings from the AA-FAIM cohort.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {9},
number = {3},
pages = {e12414},
pmid = {37752907},
issn = {2352-8737},
abstract = {INTRODUCTION: It is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low-burden disease markers, plasma amyloid beta (Aβ)42/40, and intra-individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults.

METHODS: Two hundred fifty-seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants' z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aβ42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aβ42/40.

RESULTS: IICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aβ42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aβ42/40 was associated with faster cognitive declines over time.

DISCUSSION: Our results are promising as they extend existing findings to an Black American sample using low-cost, low-burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research.},
}

@article {pmid37751459,
year = {2023},
author = {Stolzenburg, LR and Esmaeeli, S and Kulkarni, AS and Murphy, E and Kwon, T and Preiss, C and Bahnassawy, L and Stender, JD and Manos, JD and Reinhardt, P and Rahimov, F and Waring, JF and Ramathal, CY},
title = {Functional characterization of a single nucleotide polymorphism associated with Alzheimer's disease in a hiPSC-based neuron model.},
journal = {PloS one},
volume = {18},
number = {9},
pages = {e0291029},
pmid = {37751459},
issn = {1932-6203},
abstract = {Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.},
}

@article {pmid37750713,
year = {2023},
author = {Walker, A and Czyz, DM},
title = {Oh my gut! Is the microbial origin of neurodegenerative diseases real?.},
journal = {Infection and immunity},
volume = {},
number = {},
pages = {e0043722},
doi = {10.1128/iai.00437-22},
pmid = {37750713},
issn = {1098-5522},
abstract = {There is no cure or effective treatment for neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's or Parkinson's diseases, mainly because the etiology of these diseases remains elusive. Recent data suggest that unique changes in the gut microbial composition are associated with these ailments; however, our current understanding of the bacterial role in the pathogenesis of PCDs is hindered by the complexity of the microbial communities associated with specific microbiomes, such as the gut, oral, or vaginal microbiota. The composition of these specific microbiomes is regarded as a unique fingerprint affected by factors such as infections, diet, lifestyle, and antibiotics. All of these factors also affect the severity of neurodegenerative diseases. The majority of studies that reveal microbial contribution are correlational, and various models, including worm, fly, and mouse, are being utilized to decipher the role of individual microbes that may affect disease onset and progression. Recent evidence from across model organisms and humans shows a positive correlation between the presence of gram-negative enteropathogenic bacteria and the pathogenesis of PCDs. While these correlational studies do not provide a mechanistic explanation, they do reveal contributing bacterial species and provide an important basis for further investigation. One of the lurking concerns related to the microbial contribution to PCDs is the increasing prevalence of antibiotic resistance and poor antibiotic stewardship, which ultimately select for proteotoxic bacteria, especially the gram-negative species that are known for intrinsic resistance. In this review, we summarize what is known about individual microbial contribution to PCDs and the potential impact of increasing antimicrobial resistance.},
}

@article {pmid37749927,
year = {2023},
author = {Nam, H and Kim, B and Lee, Y and Choe, HK and Yu, SW},
title = {Presenilin 2 N141I Mutation Induces Hyperimmunity by Immune Cell-specific Suppression of REV-ERBα without Altering Central Circadian Rhythm.},
journal = {Experimental neurobiology},
volume = {32},
number = {4},
pages = {259-270},
doi = {10.5607/en23012},
pmid = {37749927},
issn = {1226-2560},
abstract = {Circadian rhythm is a 24-hour cycle of behavioral and physiological changes. Disrupted sleep-wake patterns and circadian dysfunction are common in patients of Alzheimer Disease (AD) and are closely related with neuroinflammation. However, it is not well known how circadian rhythm of immune cells is altered during the progress of AD. Previously, we found presenilin 2 (Psen2) N141I mutation, one of familial AD (FAD) risk genes, induces hyperimmunity through the epigenetic repression of REV-ERBα expression in microglia and bone marrow-derived macrophage (BMDM) cells. Here, we investigated whether repression of REV-ERBα is associated with dysfunction of immune cell-endogenous or central circadian rhythm by analyses of clock genes expression and cytokine secretion, bioluminescence recording of rhythmic PER2::LUC expression, and monitoring of animal behavioral rhythm. Psen2 N141I mutation down-regulated REV-ERBα and induced selective over-production of IL-6 (a well-known clock-dependent cytokine) following the treatment of toll-like receptor (TLR) ligands in microglia, astrocytes, and BMDM. Psen2 N141I mutation also lowered amplitude of intrinsic daily oscillation in these immune cells representatives of brain and periphery. Of interest, however, the period of daily rhythm remained intact in immune cells. Furthermore, analyses of the central clock and animal behavioral rhythms revealed that central clock remained normal without down-regulation of REV-ERBα. These results suggest that Psen2 N141I mutation induces hyperimmunity mainly through the suppression of REV-ERBα in immune cells, which have lowered amplitude but normal period of rhythmic oscillation. Furthermore, our data reveal that central circadian clock is not affected by Psen2 N141I mutation.},
}

@article {pmid37749398,
year = {2023},
author = {Xiu, H and Liu, F and Hou, Y and Chen, X and Tu, S},
title = {High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on global cognitive function of elderly in mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {37749398},
issn = {1590-3478},
abstract = {OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a non-invasive brain stimulation technique used to improve cognitive deficits in patients with Alzheimer's disease (AD). This systematic review and meta-analysis aimed to evaluate the efficacy of HF-rTMS in improving global cognitive function rehabilitation in elderly patients with mild to moderate AD.

METHODS: A detailed literature search of publications using ten databases (Chinese: Wanfang, VIP Periodical, SinoMed, the Chinese National Knowledge Infrastructure; English: PubMed, Embase, OVID, Web of Science, Cochrane Library, and EBSCOhost) was performed to identify English and Chinese language articles published up to December 2022. We only included randomized controlled trials (RCTs) that evaluate the effect of HF-rTMS on elderly patients with mild to moderate AD. The retrieved studies were carefully reviewed, extracted data, and assessed quality.

RESULTS: Seventeen studies, including 1161 elderly patients with mild to moderate AD, were included in this meta-analysis. Compared to the control group, HF-rTMS could increase MMSE (mean difference [MD] = 3.64; 95%CI 1.86-5.42; P < 0.0001), MoCA (MD = 3.69; 95%CI 1.84-5.54; P < 0.0001), P300 amplitude (MD = 1.09; 95%CI 0.45-1.72; P = 0.0008), and total effective rate scores (MD = 3.64; 95% CI 2.14-6.18; P < 0.00001) while decreasing ADAS-Cog (MD =  - 3.53; 95%CI - 4.91- - 2.15; P < 0.00001) and P300 latency scores (MD =  - 38.32; 95%CI - 72.40- - 4.24; P = 0.03). Our study showed that HF-rTMS could improve the global cognitive function of elderly patients with mild to moderate AD.

CONCLUSION: HF-rTMS can improve global cognitive function in elderly patients with mild to moderate AD, which is an effective and safe rehabilitation treatment tool for AD patients.},
}

@article {pmid37749371,
year = {2023},
author = {Mariner, BL and Rodriguez, AS and Heath, OC and McCormick, MA},
title = {Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {37749371},
issn = {2509-2723},
support = {5P20GM121176//National Institute of Health/ ; R01AG07077601//National Institute of Health/ ; },
abstract = {We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington's disease cell models, but there are few known pharmacological enhancers of the UPS. Additionally, we see separate ATF4 dependent upregulation of macroautophagy upon treatment with tRNA synthetase inhibitors. Protein degradation is an essential cellular process linked to many important human diseases of aging such as Alzheimer's disease and Huntington's disease. These drugs' ability to enhance proteostasis more broadly could have wide-ranging implications in the treatment of important age-related neurodegenerative diseases.},
}

@article {pmid37749233,
year = {2023},
author = {Lepinay, E and Cicchetti, F},
title = {Tau: a biomarker of Huntington's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {37749233},
issn = {1476-5578},
support = {35059//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; PJT-162164//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; PJT-168865//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Developing effective treatments for patients with Huntington's disease (HD)-a neurodegenerative disorder characterized by severe cognitive, motor and psychiatric impairments-is proving extremely challenging. While the monogenic nature of this condition enables to identify individuals at risk, robust biomarkers would still be extremely valuable to help diagnose disease onset and progression, and especially to confirm treatment efficacy. If measurements of cerebrospinal fluid neurofilament levels, for example, have demonstrated use in recent clinical trials, other proteins may prove equal, if not greater, relevance as biomarkers. In fact, proteins such as tau could specifically be used to detect/predict cognitive affectations. We have herein reviewed the literature pertaining to the association between tau levels and cognitive states, zooming in on Alzheimer's disease, Parkinson's disease and traumatic brain injury in which imaging, cerebrospinal fluid, and blood samples have been interrogated or used to unveil a strong association between tau and cognition. Collectively, these areas of research have accrued compelling evidence to suggest tau-related measurements as both diagnostic and prognostic tools for clinical practice. The abundance of information retrieved in this niche of study has laid the groundwork for further understanding whether tau-related biomarkers may be applied to HD and guide future investigations to better understand and treat this disease.},
}

@article {pmid37748987,
year = {2023},
author = {Raffard, S and de Connor, A and Freeman, D and Bortolon, C},
title = {[Recent developments in the modeling and psychological management of persecutory ideation].},
journal = {L'Encephale},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.encep.2023.08.004},
pmid = {37748987},
issn = {0013-7006},
abstract = {Persecutory ideas are a major clinical problem and are associated with impaired functioning, reduced compliance with medication and increased risk of hospitalization. Persecutory ideation is defined as the false conviction that others are threatening or conspiring against one. Although persecutory delusions are mainly described and experienced in schizophrenia spectrum disorders, they also occur in other neurological and psychiatric diagnoses including Alzheimer disease, epilepsy, depression, mania, dementia and post-traumatic stress disorder. Moreover, epidemiological data from general and clinical populations indicated that paranoid beliefs occur on a hierarchy of severity and are present to a lesser degree in the general population, with paranoid delusions representing the severe end of a continuum. In this review we focus on the important advances following a decade of research from psychological sciences, and more particularly the work of Daniel Freeman and Philippa Garety in England. Their work has demonstrated that a range of causal factors are involved in the development and maintenance of delusions beyond the traditional cognitive and behavioural models. Indeed, there is now well-validated evidence that sleep disturbances, worry proneness, reasoning biases, such as failure to consider alternative explanations or belief confirmation bias, abnormal experiences such as hallucinations, negative self-beliefs, and safety behaviours, are central factors that contribute to the paranoid phenomenon. In this review, we describe each of these causal factors in detail as well as the clinical interventions developed by Freeman and his collaborators, including the integrative and modular "Feeling Safe" intervention. Broadly speaking, the aim of this psychological intervention is for patients to relearn safety by exposing them to situations they consider as potentially dangerous after reduction of the influence of the maintenance factors described above. A recent publication showed that the Feeling Safe program led to recovery in persecutory delusions for 50% of patients having poor response to antipsychotic medication, making the intervention as the most effective psychological treatment for persecutory delusions. Finally, we will critically discuss the efficacy data from the numerous clinical studies validating its effectiveness. Prospects for the implementation of the Feeling Safe program in France also is discussed.},
}

@article {pmid37748710,
year = {2023},
author = {Chen, H and Guo, Z and Sun, Y and Dai, X},
title = {The immunometabolic reprogramming of microglia in Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {105614},
doi = {10.1016/j.neuint.2023.105614},
pmid = {37748710},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder (NDD). In the central nervous system (CNS), immune cells like microglia could reprogram intracellular metabolism to alter or exert cellular immune functions in response to environmental stimuli. In AD, microglia could be activated and differentiated into pro-inflammatory or anti-inflammatory phenotypes, and these differences in cellular phenotypes resulted in variance in cellular energy metabolism. Considering the enormous energy requirement of microglia for immune functions, the changes in mitochondria-centered energy metabolism and substrates of microglia are crucial for the cellular regulation of immune responses. Here we reviewed the mechanisms of microglial metabolic reprogramming by analyzing their flexible metabolic patterns and changes that occurred in their metabolism during the development of AD. Further, we summarized the role of drugs in modulating immunometabolic reprogramming to prevent neuroinflammation, which may shed light on a new research direction for AD treatment.},
}

@article {pmid37747555,
year = {2023},
author = {Kunnummal, SP and Khan, M},
title = {Diet-gut microbiome interaction and ferulic acid bioavailability: implications on neurodegenerative disorders.},
journal = {European journal of nutrition},
volume = {},
number = {},
pages = {},
pmid = {37747555},
issn = {1436-6215},
support = {No.5/7/1741/CH/Adhoc/2021-RBMCH//Indian Council of Medical Research/ ; },
abstract = {PURPOSE OF THE REVIEW: Ferulic acid (FA), which occurs naturally as the feruloylated sugar ester in grains, fruits, and vegetables, is critical for combating oxidative stress and alleviating neurodegenerative diseases resulting from free radical-generated protein aggregates in brain cells. However, FA cannot be absorbed in conjugated form. Therefore, strategies to improve the bioavailability of FA are gaining more importance. Ferulic acid esterases (FAE) of the gut microbiota are critical enzymes that facilitate FA release from feruloylated sugar ester conjugates and influence systemic health. This review provides insight into a nutrition-based approach to preventing neurodegenerative disorders such as Alzheimer's and Parkinson's by altering the diversity of FAE-producing gut microbiota.

RECENT FINDINGS: The human gut is a niche for a highly dense microbial population. Nutrient components and the quality of food shape the gut microbiota. Microbiota-diet-host interaction primarily involves an array of enzymes that hydrolyse complex polysaccharides and release covalently attached moieties, thereby increasing their bio-accessibility. Moreover, genes encoding polysaccharide degrading enzymes are substrate inducible, giving selective microorganisms a competitive advantage in scavenging nutrients. Nutraceutical therapy using specific food components holds promise as a prophylactic agent and as an adjunctive treatment strategy in neurotherapeutics, as it results in upregulation of polysaccharide utilisation loci containing fae genes in the gut microbiota, thereby increasing the release of FA and other antioxidant molecules and combat neurodegenerative processes.},
}

@article {pmid37747503,
year = {2023},
author = {Haußmann, R and Homeyer, P and Haußmann, M and Sauer, C and Linn, J and Donix, M and Brandt, M and Puetz, V},
title = {[Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {37747503},
issn = {1433-0407},
abstract = {OBJECTIVES: To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load.

MATERIALS AND METHODS: Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review.

RESULTS: Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634).

CONCLUSION: CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.},
}

@article {pmid37746513,
year = {2023},
author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H},
title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.},
journal = {Cureus},
volume = {15},
number = {8},
pages = {e44051},
pmid = {37746513},
issn = {2168-8184},
abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.},
}

@article {pmid37746412,
year = {2023},
author = {Shahid, K and Tamene, Y and Mody, SP and Sadiq, KO and Shivakumar, YM and Burra, E and Ramphall, S},
title = {Comparative Study of Safety and Efficacy of Angiotensin-Receptor Blockers and Anti Amyloid-ß Monoclonal Antibodies for the Treatment of Alzheimer's Disease: A Systematic Review.},
journal = {Cureus},
volume = {15},
number = {8},
pages = {e43984},
pmid = {37746412},
issn = {2168-8184},
abstract = {Amyloid-ß (Aß) plaques and Neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) pathology. Recent advances to find a cure for AD have led to the exploration of Anti-Aß monoclonal antibodies and angiotensin-receptor blockers (ARBs). The antibodies can decrease plaque formation or remove already formed plaques. ARBs increase angiotensin II (AT2) levels and decrease the effect of AT2 on the AT1 receptor (AT1R). This systematic analysis reviews evidence of monoclonal antibodies (Aducanumab, Lecanemab, Donanemab, and Solanezumab) and ARBs in managing AD. An in-depth methodical search was conducted across PubMed, Science Direct, and Mendeley. PRISMA 2020 guidelines were followed for this study. Randomized control trials for antibodies and ARBs and one retrospective cohort study were included. The comparison was made among studies that shared similar measured outcomes. Antibodies were found to be more effective than ARBs, with Aducanumab and Lecanemab being the most effective. ARBs, on the other hand, were found to be the safer choice. Further trials of longer duration and larger sample sizes are needed to explore both groups' long-term safety and efficacy.},
}

@article {pmid37745304,
year = {2023},
author = {Yokota, M and Yoshino, Y and Hosoi, M and Hashimoto, R and Kakuta, S and Shiga, T and Ishikawa, KI and Okano, H and Hattori, N and Akamatsu, W and Koike, M},
title = {Reduced ER-mitochondrial contact sites and mitochondrial Ca[2+] flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.},
journal = {Frontiers in cell and developmental biology},
volume = {11},
number = {},
pages = {1171440},
pmid = {37745304},
issn = {2296-634X},
abstract = {Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca[2+] flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.},
}

@article {pmid37745051,
year = {2023},
author = {Grabowska, ME and Huang, A and Wen, Z and Li, B and Wei, WQ},
title = {Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review.},
journal = {Frontiers in pharmacology},
volume = {14},
number = {},
pages = {1257700},
pmid = {37745051},
issn = {1663-9812},
abstract = {Background: Alzheimer's disease (AD) is a debilitating neurodegenerative condition with few treatment options available. Drug repurposing studies have sought to identify existing drugs that could be repositioned to treat AD; however, the effectiveness of drug repurposing for AD remains unclear. This review systematically analyzes the progress made in drug repurposing for AD throughout the last decade, summarizing the suggested drug candidates and analyzing changes in the repurposing strategies used over time. We also examine the different types of data that have been leveraged to validate suggested drug repurposing candidates for AD, which to our knowledge has not been previous investigated, although this information may be especially useful in appraising the potential of suggested drug repurposing candidates. We ultimately hope to gain insight into the suggested drugs representing the most promising repurposing candidates for AD. Methods: We queried the PubMed database for AD drug repurposing studies published between 2012 and 2022. 124 articles were reviewed. We used RxNorm to standardize drug names across the reviewed studies, map drugs to their constituent ingredients, and identify prescribable drugs. We used the Anatomical Therapeutic Chemical (ATC) Classification System to group drugs. Results: 573 unique drugs were proposed for repurposing in AD over the last 10 years. These suggested repurposing candidates included drugs acting on the nervous system (17%), antineoplastic and immunomodulating agents (16%), and drugs acting on the cardiovascular system (12%). Clozapine, a second-generation antipsychotic medication, was the most frequently suggested repurposing candidate (N = 6). 61% (76/124) of the reviewed studies performed a validation, yet only 4% (5/124) used real-world data for validation. Conclusion: A large number of potential drug repurposing candidates for AD has accumulated over the last decade. However, among these drugs, no single drug has emerged as the top candidate, making it difficult to establish research priorities. Validation of drug repurposing hypotheses is inconsistently performed, and real-world data has been critically underutilized for validation. Given the urgent need for new AD therapies, the utility of real-world data in accelerating identification of high-priority candidates for AD repurposing warrants further investigation.},
}

@article {pmid37743478,
year = {2023},
author = {Toles, M and Kistler, C and Lin, FC and Lynch, M and Wessell, K and Mitchell, SL and Hanson, LC},
title = {Palliative care for persons with late-stage Alzheimer's and related dementias and their caregivers: protocol for a randomized clinical trial.},
journal = {Trials},
volume = {24},
number = {1},
pages = {606},
pmid = {37743478},
issn = {1745-6215},
support = {1R01AG065394-01A1/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Limited access to specialized palliative care exposes persons with late-stage Alzheimer's disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program.

METHODS: The study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage.

DISCUSSION: The study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04948866. Registered on July 2, 2021.},
}

@article {pmid37743414,
year = {2023},
author = {Williamson, J and James, SA and Mukli, P and Yabluchanskiy, A and Wu, DH and Sonntag, W and , and Yang, Y},
title = {Sex difference in brain functional connectivity of hippocampus in Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {37743414},
issn = {2509-2723},
support = {U54GM104938/GM/NIGMS NIH HHS/United States ; P20GM125528/GM/NIGMS NIH HHS/United States ; T32AG052363/AG/NIA NIH HHS/United States ; P30AG050911/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD), affecting nearly 6.5 million people, is the fifth leading cause of death in individuals 65 years or older in the USA. Prior research has shown that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, research from our lab found that functional connectivity from the hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females with mild cognitive impairment. The aim of this study was to extend our understanding to individuals with AD and to determine if these potential sex-specific functional connectivity biomarkers extend through different disease stages. The resting state fMRI and T2 MRI of cognitively normal individuals (n = 32, female = 16) and individuals with AD (n = 32, female = 16) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that males had a significantly stronger interhemispheric functional connectivity between the left and right hippocampus compared to females. These results improve our current understanding of the role of the hippocampus in sex differences in AD. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex-specific precision medicine for improved AD treatment.},
}

@article {pmid37742657,
year = {2023},
author = {Alkon, DL and Sun, MK and Tuchman, AJ and Thompson, RE},
title = {Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-230868},
pmid = {37742657},
issn = {1875-8908},
abstract = {BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies.

OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing.

METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms.

RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit.

CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.},
}

@article {pmid37741687,
year = {2023},
author = {Jacobson, KA and Suresh, RR and Oliva, P},
title = {A2A adenosine receptor agonists, antagonists, inverse agonists and partial agonists.},
journal = {International review of neurobiology},
volume = {170},
number = {},
pages = {1-27},
doi = {10.1016/bs.irn.2023.08.001},
pmid = {37741687},
issn = {2162-5514},
abstract = {The Gs-coupled A2A adenosine receptor (A2AAR) has been explored extensively as a pharmaceutical target, which has led to numerous clinical trials. However, only one selective A2AAR agonist (regadenoson, Lexiscan) and one selective A2AAR antagonist (istradefylline, Nouriast) have been approved by the FDA, as a pharmacological agent for myocardial perfusion imaging (MPI) and as a cotherapy for Parkinson's disease (PD), respectively. Adenosine is widely used in MPI, as Adenoscan. Despite numerous unsuccessful clinical trials, medicinal chemical activity around A2AAR ligands has accelerated recently, particularly through structure-based drug design. New drug-like A2AAR antagonists for PD and cancer immunotherapy have been identified, and many clinical trials have ensued. For example, imaradenant (AZD4635), a compound that was designed computationally, based on A2AAR X-ray structures and biophysical mapping. Mixed A2AAR/A2BAR antagonists are also hopeful for cancer treatment. A2AAR antagonists may also have potential as neuroprotective agents for treatment of Alzheimer's disease.},
}

@article {pmid37740921,
year = {2023},
author = {Wagemann, O and Li, Y and Hassenstab, J and Aschenbrenner, AJ and McKay, NS and Gordon, BA and Benzinger, TLS and Xiong, C and Cruchaga, C and Renton, AE and Perrin, RJ and Berman, SB and Chhatwal, JP and Farlow, MR and Day, GS and Ikeuchi, T and Jucker, M and Lopera, F and Mori, H and Noble, JM and Sánchez-Valle, R and Schofield, PR and Morris, JC and Daniels, A and Levin, J and Bateman, RJ and McDade, E and Llibre-Guerra, JJ and , },
title = {Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13460},
pmid = {37740921},
issn = {1552-5279},
support = {U19AG032438/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD).

METHODS: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography ([11] C-PiB PET) and structural magnetic resonance imaging (MRI).

RESULTS: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences.

DISCUSSION: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.},
}

@article {pmid37737298,
year = {2023},
author = {Grayson, JM and Short, SM and Lee, CJ and Park, N and Marsac, C and Sette, A and Lindestam Arlehamn, CS and Leng, XI and Lockhart, SN and Craft, S},
title = {T cell exhaustion is associated with cognitive status and amyloid accumulation in Alzheimer's disease.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {15779},
pmid = {37737298},
issn = {2045-2322},
abstract = {Studies over the last 100 years have suggested a link between inflammation, infectious disease, and Alzheimer's Disease (AD). Understanding how the immune system changes during the development of AD may facilitate new treatments. Here, we studied an aging cohort who had been assessed for AD pathology with amyloid positron emission tomography and cognitive testing, and conducted high dimensional flow cytometry on peripheral blood mononuclear and cerebrospinal fluid cells. Participants were assigned a classification of being amyloid negative cognitively normal, amyloid positive cognitively normal (APCN), or amyloid positive mild cognitive impairment (APMCI), an early stage of AD. We observed major alterations in the peripheral innate immune system including increased myeloid and plasmacytoid dendritic cells in the blood of APMCI participants. When the adaptive immune system was examined, amyloid positive participants, regardless of cognitive status, had increased CD3[+] T cells. Further analyses of CD4[+] and CD8[+] T cells revealed that APMCI participants had an increase in more differentiated phenotype T cells, such as effector memory and effector memory CD45RA expressing (TEMRA), compared to those with normal cognition. When T cell function was measured, we observed that T cells from APCN participants had increased IFNγ[+]GzB[-] producing cells compared to the other participants. In contrast, we demonstrate that APMCI participants had a major increase in T cells that lacked cytokine production following restimulation and expressed increased levels of PD-1 and Tox, suggesting these are exhausted cells. Rejuvenation of these cells may provide a potential treatment for AD.},
}

@article {pmid37736681,
year = {2023},
author = {Zeng, Y and Cao, S and Li, N and Tang, J and Lin, G},
title = {Identification of key lipid metabolism-related genes in Alzheimer's disease.},
journal = {Lipids in health and disease},
volume = {22},
number = {1},
pages = {155},
pmid = {37736681},
issn = {1476-511X},
support = {81900634//National Natural Science Foundation for Distinguished Young Scholars of China/ ; 2021JJ40947//Natural Sciences Foundation of Hunan Province for Distinguished Young Scholars/ ; kq2208356//Natural Science Foundation of Changsha City/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression.

METHODS: Comprehensive analyses were performed to determine key DELMRGs in AD compared to controls in GSE122063 dataset from Gene Expression Omnibus. Additionally, the ssGSEA algorithm was utilized for estimating immune cell levels. Subsequently, correlations between key DELMRGs and each immune cell were calculated specifically in AD samples. The key DELMRGs expression levels were validated via two external datasets. Furthermore, gene set enrichment analysis (GSEA) was utilized for deriving associated pathways of key DELMRGs. Additionally, miRNA-TF regulatory networks of the key DELMRGs were constructed using the miRDB, NetworkAnalyst 3.0, and Cytoscape software. Finally, based on key DELMRGs, AD samples were further segmented into two subclusters via consensus clustering, and immune cell patterns and pathway differences between the two subclusters were examined.

RESULTS: Seventy up-regulated and 100 down-regulated DELMRGs were identified. Subsequently, three key DELMRGs (DLD, PLPP2, and PLAAT4) were determined utilizing three algorithms [(i) LASSO, (ii) SVM-RFE, and (iii) random forest]. Specifically, PLPP2 and PLAAT4 were up-regulated, while DLD exhibited downregulation in AD cerebral cortex tissue. This was validated in two separate external datasets (GSE132903 and GSE33000). The AD group exhibited significantly altered immune cell composition compared to controls. In addition, GSEA identified various pathways commonly associated with three key DELMRGs. Moreover, the regulatory network of miRNA-TF for key DELMRGs was established. Finally, significant differences in immune cell levels and several pathways were identified between the two subclusters.

CONCLUSION: This study identified DLD, PLPP2, and PLAAT4 as key DELMRGs in AD progression, providing novel insights for AD prevention/treatment.},
}

@article {pmid37736506,
year = {2023},
author = {Esmaealzadeh, D and Moodi Ghalibaf, A and Shariati Rad, M and Rezaee, R and Razavi, BM and Hosseinzadeh, H},
title = {Pharmacological effects of Safranal: An updated review.},
journal = {Iranian journal of basic medical sciences},
volume = {26},
number = {10},
pages = {1131-1143},
pmid = {37736506},
issn = {2008-3866},
abstract = {Safranal (a monoterpene aldehyde) is the major volatile component of saffron which is responsible for the saffron unique odor. Several studies have shown the pharmacological activities of safranal including anti-oxidant, anti-inflammatory, cardioprotective, neuroprotective, nephroprotective, gastrointestinal protective, etc. This study was designed to review the pharmacological and medical effects of safranal and up-to-date previous knowledge. Moreover, some patents related to the pharmacological effects of safranal were gathered. Therefore, electronic databases including Web of Sciences, Scopus, and Pubmed for pharmacological effects and US patent, Patentscope, and Google Patent for patents were comprehensively searched by related English keywords from 2010 to June 2022. According to our review, most of the studies are related to the safranal effects on CNS such as antianxiety, analgesic, anticonvulsant, antiischemic, anti-tremor, memory enhancement and its protective effects on neurodegenerative disorders such as Alzheimer's, Parkinson and Huntington diseases. Other effects of safranal are antiasthmatic, antihypertensive, antiaging, anticataract, etc. Moreover, the protective effects of this agent on metabolic syndrome and diabetic nephropathy have been shown. Different mechanisms including anti-oxidant, anti-inflammatory, muscle relaxation, antiapoptotic, and regulatory effects on the genes and proteins expression related to signaling pathways of oxidative stress, inflammation, apoptosis, proliferation, etc. are involved in safranal pharmacological effects. Some patents for the prevention and/or treatment of different diseases such as liver cancer, sleep disorder, depression, cognitive disorder, obesity and PMS were also included. Based on the documents, safranal is considered a promising therapeutic agent although more clinical studies are needed to verify the beneficial effects of safranal in humans.},
}

@article {pmid37736505,
year = {2023},
author = {Aghaei Delche, N and Kheiri, R and Ghorbani Nejad, B and Sheikhi, M and Razavi, MS and Rahimzadegan, M and Salmasi, Z},
title = {Recent progress in the intranasal PLGA-based drug delivery for neurodegenerative diseases treatment.},
journal = {Iranian journal of basic medical sciences},
volume = {26},
number = {10},
pages = {1107-1119},
pmid = {37736505},
issn = {2008-3866},
abstract = {One of the most challenging problems of the current treatments of neurodegenerative diseases is related to the permeation and access of most therapeutic agents to the central nervous system (CNS), prevented by the blood-brain barrier (BBB). Recently, intranasal (IN) delivery has opened new prospects because it directly delivers drugs for neurological diseases into the brain via the olfactory route. Recently, PLGA-based nanocarriers have attracted a lot of interest for IN delivery of drugs. This review gathered clear and concise statements of the recent progress of the various developed PLGA-based nanocarriers for IN drug delivery in brain diseases including Alzheimer's, Parkinson's, brain tumors, ischemia, epilepsy, depression, and schizophrenia. Subsequently, future perspectives and challenges of PLGA-based IN administration are discussed briefly.},
}

@article {pmid37736174,
year = {2023},
author = {Kargbo, RB},
title = {New Horizons in Cancer Treatment: A Closer Look at Novel PI3Kα Inhibitors.},
journal = {ACS medicinal chemistry letters},
volume = {14},
number = {9},
pages = {1138-1140},
pmid = {37736174},
issn = {1948-5875},
abstract = {Phosphoinositide 3-kinase (PI3K), a lipid messenger in cellular biology, regulates numerous cellular responses, including cell survival and migration. Abnormal activation of PI3K has been identified in many human tumors, implicating it as a pivotal point in cancer research. PI3K inhibitors have shown promise in controlling tumor progression and chemotherapy resistance. However, challenges like cutaneous adverse effects require further research. The PI3K signaling pathway's role in cellular processes, such as aging and Alzheimer's disease progression, also signifies its importance in drug development for aging-related diseases. Future research promises innovative therapeutic strategies targeting PI3K in managing cancer, aging, and neurodegenerative diseases. This Patent Highlight showcases compounds and compositions that may enlarge the PI3K inhibitory therapeutic window-effectively inhibiting the target in cancer cells while reducing toxicity in patients.},
}

@article {pmid37735992,
year = {2023},
author = {Li, L and Jin, M and Tan, J and Xiao, B},
title = {NcRNAs: A synergistically antiapoptosis therapeutic tool in Alzheimer's disease.},
journal = {CNS neuroscience & therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1111/cns.14476},
pmid = {37735992},
issn = {1755-5949},
support = {//Open Project Program of Guangxi Key Laboratory of Brain and Cognitive Neuroscience (GKLBCN-20190103, GKLBCN-20190105-04, and GKLBCN-202106-02)/ ; //Young and Middle aged Teachers' Basic Research Ability Improvement Project of Universities in Guangxi (2023KY0522 and 2023KY0541)/ ; },
abstract = {AIMS: The aim of this review is to systematically summarize and analyze the noncoding RNAs (ncRNAs), especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the cell apoptosis among Alzheimer's disease (AD) in recent years to demonstrate their value in the diagnosis and treatment of AD.

METHODS: We systematically summarized in vitro and in vivo studies focusing on the ncRNAs in the regulation of cell apoptosis among AD in PubMed, ScienceDirect, and Google Scholar.

RESULTS: We discover three patterns of ncRNAs (including 'miRNA-mRNA', 'lncRNA-miRNA-mRNA', and 'circRNA-miRNA-mRNA') form the ncRNA-based regulatory networks in regulating cell apoptosis in AD.

CONCLUSIONS: This review provides a future diagnosis and treatment strategy for AD patients based on ncRNAs.},
}

@article {pmid37735671,
year = {2023},
author = {Fan, LY and Yang, J and Liu, RY and Kong, Y and Guo, GY and Xu, YM},
title = {Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.},
journal = {Journal of translational medicine},
volume = {21},
number = {1},
pages = {649},
pmid = {37735671},
issn = {1479-5876},
support = {U1904207//National Natural Science Foundation of China/ ; 2017YFA0105003//National Key R&D Program of China/ ; 2020-PT310-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; YXKC2021062//Innovative and Scientific and Technological Talents Training Project of Henan Province/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them.

METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database (http://string-db.org). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map (https://clue.io).

RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS.

CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.},
}

@article {pmid37735155,
year = {2023},
author = {Tu, Z and Yan, S and Han, B and Li, C and Liang, W and Lin, Y and Ding, Y and Wei, H and Wang, L and Xu, H and Ye, J and Li, B and Li, S and Li, XJ},
title = {Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys.},
journal = {Signal transduction and targeted therapy},
volume = {8},
number = {1},
pages = {358},
pmid = {37735155},
issn = {2059-3635},
support = {81830032//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31872779//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81922026//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82071421//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82171244//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aβ oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aβ accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aβ oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aβ oligomers in the monkey spinal cord. These Aβ oligomers were recognized by several antibodies to Aβ1-42 and contributed to neurodegeneration. However, the generation of Aβ oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aβ oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aβ pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.},
}

@article {pmid37735138,
year = {2023},
author = {Rostgaard, N and Jul, PH and Garmer, M and Volbracht, C},
title = {Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice.},
journal = {Journal of integrative neuroscience},
volume = {22},
number = {5},
pages = {135},
doi = {10.31083/j.jin2205135},
pmid = {37735138},
issn = {0219-6352},
abstract = {BACKGROUND: Tauopathies such as Alzheimer's disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked β-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate tau phosphorylation and aggregation and N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins.

METHODS: We investigated effects of the OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures and in rTg4510 mice. The rTg4510 mice overexpress human tau harboring the P301L mutation and display an age-dependent progression of tau pathology including hyperphosphorylated tau species and NFTs. Aged rTg4510 mice exhibit a non-mnemonic behavioral defect involving a hyperactive phenotype that is associated with the progression of tau pathology.

RESULTS: Thiamet G increased overall O-GlcNAc levels and crossed the blood brain barrier in rTg4510 mice. The free fraction of Thiamet G in the brain was 22-fold above the half maximal effective concentration (EC50) measured in rTg4510 primary neurons. Chronic Thiamet G treatment (18 weeks) initiated in young 6 week old rTg4510 mice increased brain O-GlcNAc levels and this corresponded with a significant reduction in soluble and insoluble hyperphosphorylated tau in aged 24 week old rTg4510 mice. Levels of normally phosphorylated P301L tau were not altered under these conditions. Reduction of hyperphosphorylated tau species by increased O-GlcNAcylation was associated with significant attenuation of hyperactivity in 24 week old rTg4510 mice.

CONCLUSIONS: Our findings support the pharmacological inhibition of OGA as a potential therapeutic approach for the treatment of AD and other tauopathies.},
}

@article {pmid37734531,
year = {2023},
author = {Kamranfar, F and Jaktaji, RP and Shirani, K and Jamshidi, A and Samiei, F and Arjmand, A and Khoramjouy, M and Faizi, M and Pourahmad, J},
title = {Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {137491},
doi = {10.1016/j.neulet.2023.137491},
pmid = {37734531},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.},
}

@article {pmid37734258,
year = {2023},
author = {Basagni, F and Ortega, JA and Bertozzi, SM and Armirotti, A and Summa, M and Bertorelli, R and Bartolini, M and Mellor, IR and Bedeschi, M and Bottegoni, G and Lembo, V and Minarini, A and Cavalli, A and Rosini, M},
title = {Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties.},
journal = {European journal of medicinal chemistry},
volume = {261},
number = {},
pages = {115803},
doi = {10.1016/j.ejmech.2023.115803},
pmid = {37734258},
issn = {1768-3254},
abstract = {Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations.},
}

@article {pmid37735123,
year = {2023},
author = {Chen, P and Guo, Z and Zhou, B},
title = {Neuroprotective Potential of Punicalagin, a Natural Component of Pomegranate Polyphenols: A Review.},
journal = {Journal of integrative neuroscience},
volume = {22},
number = {5},
pages = {113},
doi = {10.31083/j.jin2205113},
pmid = {37735123},
issn = {0219-6352},
support = {31770381//National Natural Science Foundation of China/ ; WDCM2022006//Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine)/ ; },
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are major health problems worldwide. To date, available remedies against NDs are limited. In fact, current treatment options include drug intervention and nutritional therapy, which mainly focus on the repair of neuronal damage and functional monitoring. However, these treatments do not completely alleviate disease symptoms. Recently, eliminating harmful molecules, such as reactive oxygen species, and inhibiting neuroinflammation have become potential strategies recommended by many researchers. Accordingly, remarkable interest has been generated in recent years regarding natural products, including polyphenols, that provide neuroprotective effects. In this review, we aimed to provide experimental evidence of the therapeutic potential of punicalagin (PUN), a prevailing compound in pomegranate polyphenols with antioxidant activity. Overall, the chemistry, methods of determination, characteristics of metabolism, transformation mechanisms of action, and neuroprotective effects of PUN on NDs are summarised to provide a scientific basis for elucidating the therapeutic mechanisms and targets of NDs.},
}

@article {pmid37735117,
year = {2023},
author = {Ju, Y and Zhao, L and Li, S and Zhao, Q},
title = {The Role of Pyroptosis in Alzheimer's Disease.},
journal = {Journal of integrative neuroscience},
volume = {22},
number = {5},
pages = {129},
doi = {10.31083/j.jin2205129},
pmid = {37735117},
issn = {0219-6352},
support = {20200404076YY//Fund of Science and Technology Development Project of Jilin Province/ ; },
abstract = {Pyroptosis is a type of regulated cell death that relies on caspases, vesicles, and the cleavage of gasdermin proteins (which create pores in the cell membrane). The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, which is involved in this process, is the most widely studied inflammasome. Caspase-1 activates pro-inflammatory cytokines, such as IL-1β and IL-18. Gasdermin D (GSDMD) is the most important executive protein. GSDMD, a substrate rather than an upstream protease, determines the occurrence of pyroptosis. Pyroptosis is essential for maintaining body homeostasis, but excessive or poorly regulated cell death can aggravate the inflammatory response. Undoubtedly, this will be an important direction for future research on Alzheimer's disease (AD). Here, we review recent research progress on the morphological characteristics, molecular mechanisms, and role of pyroptosis in the context of AD, thereby providing new directions for identifying potential disease biomarkers and treatment strategies for AD.},
}

@article {pmid37733209,
year = {2023},
author = {Perna, A and Montine, KS and White, LR and Montine, TJ and Cholerton, BA},
title = {Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {},
pmid = {37733209},
issn = {1878-7479},
support = {UF1 AG057707/AG/NIA NIH HHS/United States ; UF1 AG053983/AG/NIA NIH HHS/United States ; },
abstract = {Neurodegenerative dementia can result from multiple underlying abnormalities, including neurotransmitter imbalances, protein aggregation, and other neurotoxic events. A major complication in identifying effective treatment targets is the frequent co-occurrence of multiple neurodegenerative processes, occurring either in parallel or sequentially. The path towards developing effective treatments for Alzheimer's disease (AD) and other dementias has been relatively slow and until recently has focused on disease symptoms. Aducanumab and lecanemab, recently approved by the FDA, are meant to target disease structures but have only modest benefit on symptom progression and remain unproven in reversing or preventing dementia. A third, donanemab, appears more promising but awaits FDA approval. Ongoing trials include potential cognition enhancers, new combinations of known drugs for synergistic effects, prodrugs with less toxicity, and increasing interest in drugs targeting neuroinflammation or microbiome. Scientific and technological advances offer the opportunity to move in new therapy directions, such as modifying microglia to prevent or suppress underlying disease. A major challenge, however, is that underlying comorbidities likely influence the effectiveness of therapies. Indeed, the full range of comorbidity, today only definitively identified postmortem, likely contributes to failed clinical trials and overmedication of older adults, since it is difficult to exclude (during life) people unlikely to respond. Our current knowledge thus signals that a paradigm shift towards individualized and multimodal treatments is necessary to effectively advance the field of dementia therapeutics.},
}

@article {pmid37733170,
year = {2023},
author = {Negahdary, M and Buoro, RM and Bacil, RP and Santos, BG and Angnes, L},
title = {Design of an electrochemical aptasensor in the presence of an array of gold nanostructure and a GO-MWCNTs nanocomposite: application in diagnosis of Alzheimer's disease.},
journal = {Mikrochimica acta},
volume = {190},
number = {10},
pages = {409},
pmid = {37733170},
issn = {1436-5073},
support = {2019/27021-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2017/13137-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2014/50867-3//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {Alzheimer's disease (AD) is considered one of the main progressive chronic diseases in elderly individuals. Early diagnosis using related biomarkers, specifically beta-amyloid peptide (Aβ), allows finding expected treatment routes. Here, we developed an electrochemical aptasensing platform for AD by employing a glassy carbon electrode (GCE) modified with a layer of jagged gold (JG) nanostructure (diameter: 60-185 nm) and graphene oxide-carboxylic acid functionalized multiwalled carbon nanotubes (GO-c-MWCNTs) nanocomposite. These surface modifications acted as the signal amplifier and provided an optimum nano-interface substrate for immobilizing aptamer strands. The measurements of Aβ were performed via differential pulse voltammetry (DPV), and the aptasensor detected the analyte in a linear range from 0.1 pg mL[-1] to 1 ng mL[-1], with an estimated limit of detection (LOD) of about 0.088 pg mL[-1] (S/N = 3). The aptasensor showed sufficient stability (11 days), reversibility (three times), and reproducibility (five times re-fabrication with relative standard deviation (RSD): 1.27). The potential interfering agents showed negligible impact on the sensing performance. Finally, the application of the aptasensor was evaluated in the presence of 10 serum samples, and the recovery values were from 93 to 110.1%.},
}

@article {pmid37733020,
year = {2023},
author = {Ostovan, VR and Baberi, N and Farokhi, MR and Moezi, L and Pirsalami, F and Soukhaklari, R and Moosavi, M},
title = {Cholinergic deficit induced memory retrieval impairment and hippocampal CaMKII-alpha deregulation is counteracted by sub-chronic agmatine treatment in mice.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01616412.2023.2257417},
pmid = {37733020},
issn = {1743-1328},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII-α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII-α signaling. In addition, the effect of sub-chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII-α deregulation was investigated in mice. Adult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII-α and beta actin proteins. The results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII-α. Sub-chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII-α. This study suggests that hippocampal CaMKII-α might play a role in scopolamine induced amnesia and sub-chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII-α protein.},
}

@article {pmid37732619,
year = {2023},
author = {Deliyannides, DA and Graff, JA and Niño, I and Lee, S and Husain, MM and Forester, BP and Crocco, E and Vahia, IV and Devanand, DP},
title = {Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation.},
journal = {International journal of geriatric psychiatry},
volume = {38},
number = {9},
pages = {e6002},
doi = {10.1002/gps.6002},
pmid = {37732619},
issn = {1099-1166},
support = {/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: There is ample evidence in animal models that lithium increases Brain-Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function.

OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD).

METHOD: We measured levels of BDNF in patients treated with lithium prior to and after a 12-week randomized placebo-controlled trial.

RESULTS: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function.

CONCLUSIONS: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia.},
}

@article {pmid37732313,
year = {2023},
author = {Zhang, YM and Qi, YB and Gao, YN and Chen, WG and Zhou, T and Zang, Y and Li, J},
title = {Astrocyte metabolism and signaling pathways in the CNS.},
journal = {Frontiers in neuroscience},
volume = {17},
number = {},
pages = {1217451},
pmid = {37732313},
issn = {1662-4548},
abstract = {Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.},
}

@article {pmid37732300,
year = {2023},
author = {Pless, A and Ware, D and Saggu, S and Rehman, H and Morgan, J and Wang, Q},
title = {Understanding neuropsychiatric symptoms in Alzheimer's disease: challenges and advances in diagnosis and treatment.},
journal = {Frontiers in neuroscience},
volume = {17},
number = {},
pages = {1263771},
pmid = {37732300},
issn = {1662-4548},
abstract = {Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) affect up to 97% of AD patients, with an estimated 80% of current AD patients experiencing these symptoms. Common AD-associated NPS include depression, anxiety, agitation, aggression, and apathy. The severity of NPS in AD is typically linked to the disease's progression and the extent of cognitive decline. Additionally, these symptoms are responsible for a significant increase in morbidity, mortality, caregiver burden, earlier nursing home placement, and greater healthcare expenditure. Despite their high prevalence and significant impact, there is a notable lack of clinical research on NPS in AD. In this article, we explore and analyze the prevalence, symptom manifestations, challenges in diagnosis, and treatment options of NPS associated with AD. Our literature review reveals that distinguishing and accurately diagnosing the NPS associated with AD remains a challenging task in clinical settings. It is often difficult to discern whether NPS are secondary to pathophysiological changes from AD or are comorbid psychiatric conditions. Furthermore, the availability of effective pharmaceutical interventions, as well as non-pharmacotherapies for NPS in AD, remains limited. By highlighting the advance and challenges in diagnosis and treatment of AD-associated NPS, we aspire to offer new insights into the complexity of identifying and treating these symptoms within the context of AD, and contribute to a deeper understanding of the multifaceted nature of NPS in AD.},
}

@article {pmid37732123,
year = {2023},
author = {Cisternas, P and Gherardelli, C and Gutierrez, J and Salazar, P and Mendez-Orellana, C and Wong, GW and Inestrosa, NC},
title = {Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model.},
journal = {Frontiers in endocrinology},
volume = {14},
number = {},
pages = {1237796},
pmid = {37732123},
issn = {1664-2392},
abstract = {Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aβ42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aβ42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aβ pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.},
}

@article {pmid37731744,
year = {2023},
author = {Qin, Y and Ba, L and Zhang, F and Jian, S and Tian, T and Zhang, M and Zhu, W},
title = {Multisite rTMS combined with cognitive training modulates effective connectivity in patients with Alzheimer's disease.},
journal = {Frontiers in neural circuits},
volume = {17},
number = {},
pages = {1202671},
pmid = {37731744},
issn = {1662-5110},
abstract = {PURPOSE: To investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG).

METHOD: We selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, n = 11) or sham (sham rTMS+COG, n = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with "time" as the within-subjects factor (three levels: T0, T4, and T8) and "group" as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA).

RESULTS: At the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function.

CONCLUSION: Multisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.},
}

@article {pmid37730113,
year = {2023},
author = {Wang, ZJ and Li, XR and Chai, SF and Li, WR and Li, S and Hou, M and Li, JL and Ye, YC and Cai, HY and Hölscher, C and Wu, MN},
title = {Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.},
journal = {Neuropharmacology},
volume = {240},
number = {},
pages = {109716},
doi = {10.1016/j.neuropharm.2023.109716},
pmid = {37730113},
issn = {1873-7064},
abstract = {Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using [18]FDG-PET-CT scans. We measured the expression of Aβ and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aβ plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.},
}

@article {pmid37729769,
year = {2023},
author = {Kan, CN and Huang, X and Zhang, L and Hilal, S and Reilhac, A and Tanaka, T and Venketasubramanian, N and Chen, C and Xu, X},
title = {Comorbid amyloid with cerebrovascular disease in domain-specific cognitive and neuropsychiatric disturbances: a cross-sectional memory clinic study.},
journal = {Neurobiology of aging},
volume = {132},
number = {},
pages = {47-55},
doi = {10.1016/j.neurobiolaging.2023.08.005},
pmid = {37729769},
issn = {1558-1497},
abstract = {Dementia is a multifactorial disorder that is likely influenced by both Alzheimer's disease (AD) and vascular pathologies. We evaluated domain-specific cognitive and neuropsychiatric dysfunction using a two-neuroimaging biomarker construct (beta-amyloid [Aβ] and cerebrovascular disease [CeVD]). We analyzed data from 216 memory clinic participants (mean age = 75.9 ± 6.9; 56.5% female) with neuropsychological and neuropsychiatric assessments, 3T-MRI, and Aβ-PET imaging. Structural equation modeling showed that the largest Aβ (A+) effect was on memory (B = -1.50) and apathy (B = 0.26), whereas CeVD effects were largest on language (B = -1.62) and hyperactivity (B = 0.32). Group comparisons showed that the A+C+ group had greater memory impairment (B = -1.55), hyperactivity (B = 0.79), and apathy (B = 0.74) compared to A-C+; and greater language impairment (B = -1.26) compared to A+C-. These potentially additive effects of Aβ and CeVD burden underline the importance of early detection and treatment of Aβ alongside optimal control of vascular risk factors as a potential strategy in preventing cognitive and neurobehavioral impairment.},
}

@article {pmid37729717,
year = {2023},
author = {Lane, HY and Wang, SH and Lin, CH},
title = {Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.},
journal = {Psychiatry research},
volume = {328},
number = {},
pages = {115461},
doi = {10.1016/j.psychres.2023.115461},
pmid = {37729717},
issn = {1872-7123},
abstract = {Previous studies found that an NMDA receptor (NMDAR) enhancer, sodium benzoate, improved cognitive function of patients with early-phase Alzheimer's disease (AD). Transcranial direct current stimulation (tDCS) induces NMDAR-dependent synaptic plasticity and strengthens cognitive function of AD patients. This study aimed to evaluate efficacy and safety of tDCS plus benzoate in early-phase dementia. In this 24-week randomized, double-blind, placebo-controlled trial, 97 patients with early-phase AD received 10-session tDCS during the first 2 weeks. They then took benzoate or placebo for 24 weeks. We assessed the patients using Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus Caregiver Input, Mini Mental Status Examination, Alzheimer's disease Cooperative Study scale for ADL in MCI, and a battery of additional cognitive tests. Forty-seven patients received sodium benzoate, and the other 50 placebo. The two treatment groups didn't differ significantly in ADAS-cog or other measures. Addition of benzoate to tDCS didn't get extra benefit or side effect in this study. For more thoroughly studying the potential of combining tDCS with benzoate in the AD treatment, future research should use other study designs, such as longer-term benzoate treatment, adding benzoate in the middle of tDCS trial sessions, or administering benzoate then tDCS.},
}

@article {pmid37728864,
year = {2023},
author = {Cummings, JL and Osse, AML and Kinney, JW},
title = {Alzheimer's Disease: Novel Targets and Investigational Drugs for Disease Modification.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {37728864},
issn = {1179-1950},
support = {P20GM109025/GM/NIGMS NIH HHS/United States ; U01NS093334/NS/NINDS NIH HHS/United States ; R01AG053798/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; R35AG71476/AG/NIA NIH HHS/United States ; },
abstract = {Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E [Formula: see text] 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD.},
}

@article {pmid37728579,
year = {2023},
author = {Qu, L and Li, Y and Liu, F and Fang, Y and He, J and Ma, J and Xu, T and Wang, L and Lei, P and Dong, H and Jin, L and Yang, Q and Wu, W and Sun, D},
title = {Microbiota-Gut-Brain Axis Dysregulation in Alzheimer's Disease: Multi-Pathway Effects and Therapeutic Potential.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2023.0823-2},
pmid = {37728579},
issn = {2152-5250},
abstract = {An essential regulator of neurodegenerative conditions like Alzheimer's disease (AD) is the gut microbiota. Alterations in intestinal permeability brought on by gut microbiota dysregulation encourage neuroinflammation, central immune dysregulation, and peripheral immunological dysregulation in AD, as well as hasten aberrant protein aggregation and neuronal death in the brain. However, it is unclear how the gut microbiota transmits information to the brain and how it influences brain cognition and function. In this review, we summarized the multiple pathways involved in the gut microbiome in AD and provided detailed treatment strategies based on the gut microbiome. Based on these observations, this review also discusses the problems, challenges, and strategies to address current therapeutic strategies.},
}

@article {pmid37728399,
year = {2023},
author = {Wang, H and Han, M and Li, J and Hu, Y and Chen, Y and Li, J},
title = {Versatile lipoprotein-inspired nanocomposites rescue Alzheimer's cognitive dysfunction by promoting Aβ degradation and lessening oxidative stress.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d3nr03346e},
pmid = {37728399},
issn = {2040-3372},
abstract = {The accumulation of amyloid-β (Aβ) into senile plaques and the resulting continuous oxidative stress are major pathogenic mechanisms in Alzheimer's disease (AD). In this study, we designed a lipoprotein-inspired nanoparticle to facilitate Aβ clearance and alleviate oxidative stress for the treatment of AD. Lipoprotein-like nanocomposites (RLA-rHDL@ANG) were fabricated by assembling reconstituted high density lipoprotein (rHDL) with an apoE-derived peptide (RLA) with Aβ binding and clearance capabilities, and were subsequently camouflaged using reactive oxygen species (ROS)-sensitive DSPE-TK-mPEG2000 and DSPE-TK-PEG3400-ANG with brain penetration as well as ROS scavenging ability. Immunoelectron microscopy, fluorescence colocalization, and enzyme linked immunosorbent assay, together with a thioflavin-T (ThT) fluorescence quantitative test, showed that RLA-rHDL@ANG possessed the ability of high binding affinity to both Aβ monomers and oligomers, and disintegration of pre-formed Aβ aggregates. ROS level monitoring and transmission electron microscopy (TEM) showed that RLA-rHDL@ANG possessed ROS sensitivity and consumption properties. Transcellular assay and in vivo imaging showed that RLA-rHDL@ANG effectively facilitated blood-brain barrier (BBB) penetration and intracerebral accumulation. It promoted the efficient degradation of Aβ by microglia and neurons through lysosomal transport and elimination approaches. Four-week administration of RLA-rHDL@ANG effectively reduced Aβ deposition, decreased the ROS level and improved cognitive functions in AD mice. These findings indicate that multifunctional RLA-rHDL@ANG may serve as a promising and feasible candidate for managing the progression of AD.},
}

@article {pmid37727255,
year = {2023},
author = {Lei, X and Xu, H and Wang, Y and Gao, H and Zhao, D and Zhang, J and Zhu, Z and Zuo, K and Liu, Y and Li, X and Zhang, N},
title = {Integrating Network Pharmacology and Component Analysis to Study the Potential Mechanisms of Qi-Fu-Yin Decoction in Treating Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {17},
number = {},
pages = {2841-2858},
pmid = {37727255},
issn = {1177-8881},
abstract = {PURPOSE: To elucidate the potential mechanisms of QFY for the treatment of Alzheimer's Disease (AD), and explore the effective substances of QFY.

MATERIALS AND METHODS: UPLC-LTQ-Orbitrap-MS was used to identify the chemical constituents of the serum samples and the cerebrospinal fluid samples of rats after QFY administration. Network pharmacology was used to predict potential targets and pathways of QFY against AD. The AD mice model was established by subcutaneous injection of D-gal for 8 consecutive weeks. New object recognition (NOR) and Morris water maze test (MWM) were used to evaluate the learning and memory abilities of mice. Moreover, the levels of TNF-α, IL-1β, and IL-18 in the brain hippocampus of mice were determined by ELISA. The expression of Bax, Bcl-2, Caspase-1, PSD95, SYP, ICAM-1 and MCP-1 proteins in the hippocampus was detected by Western blotting. Furthermore, qRT-PCR was used to detect the gene expressions of PSD95, SYP, M1 and M2 polarization markers of microglia, including iNOS, CD16, ARG-1, and IL-10 in the hippocampus.

RESULTS: A total of 51 prototype compounds were detected in rat serum and 15 prototype components were identified in rat cerebrospinal fluid. Behavioral experiments revealed that QFY significantly increased the recognition index, decreased the escape latency, increased the platform crossing times and increased the residence time in the target quadrant. QFY also could alleviate the ultrastructural pathological changes in the hippocampus of AD mice. Meanwhile, QFY treatment suppressed the expression of inflammatory factors, such as TNF-α, IL-1β, and IL-18. QFY improved the synaptic plasticity of the hippocampus in D-gal model mice by significantly increasing the expression of proteins and mRNAs of PSD95 and SYP.

CONCLUSION: QFY could effectively improve the learning and memory impairment of D-gal-induced AD mice by inhibiting the excessive activation of microglia, enhancing the expression of M2 microglia, inhibiting the increase of inflammatory factors, cell adhesion factors and chemokines, anti-apoptosis, and improving synaptic plasticity.},
}

@article {pmid37726834,
year = {2023},
author = {Lee, JY and Harney, DJ and Teo, JD and Kwok, JB and Sutherland, GT and Larance, M and Don, AS},
title = {The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus.},
journal = {Molecular neurodegeneration},
volume = {18},
number = {1},
pages = {63},
pmid = {37726834},
issn = {1750-1326},
support = {1100626//National Health and Medical Research Council/ ; 1162349//National Health and Medical Research Council/ ; 2002660//National Health and Medical Research Council/ ; DP210102837//Australian Research Council/ ; },
abstract = {BACKGROUND: The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases.

METHODS: Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66-104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Fibrillar C-terminal TMEM106B fragments were isolated using sarkosyl fractionation and quantified by immunoblotting.

RESULTS: Forty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. TMEM106B, a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with ageing was specific to carriers of the rs1990622-A allele in the TMEM106B gene that increases risk for frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and hippocampal sclerosis with ageing. Rs1990622-A was also associated with higher TMEM106B fibril content. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype.

CONCLUSIONS: Our study demonstrates that TMEM106B protein abundance is increased with brain ageing in humans, establishes that dementia risk allele rs1990622-A predisposes to TMEM106B fibril formation in the hippocampus, and provides the first evidence that rs1990622-A affects brain lipid homeostasis, particularly myelin lipids. Our data suggests that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.},
}

@article {pmid37726773,
year = {2023},
author = {Thabit, S and Handoussa, H and ElSayed, NS and Breitinger, HG and Breitinger, U and Wink, M},
title = {A fruit extract of Styphnolobium japonicum (L.) counteracts oxidative stress and mediates neuroprotection in Caenorhabditis elegans.},
journal = {BMC complementary medicine and therapies},
volume = {23},
number = {1},
pages = {330},
pmid = {37726773},
issn = {2662-7671},
support = {43260//Science, Technology &. Innovation Funding Authority (STDF)/ ; },
abstract = {BACKGROUND: Despite its widespread uses in Chinese and European medicine, Styphnolobium japonicum (Chinese scholar tree, formerly Sophora japonicum) has not been extensively investigated for its potential to protect against neurodegenerative processes and to promote resistance to oxidative stress. In this study, we evaluated the neuroprotective activities of a hydroalcoholic extract from Chinese scholar tree fruits that could be possibly linked to its antioxidant properties using Caenorhabditis elegans as a well-established in vivo model.

METHODS: Survival rate in mutant daf-16 and skn-1 worms, stressed by the pro-oxidant juglone and treated with the extract, was tested. Localization of the transcription factors SKN-1 and DAF-16, and expression of gst-4 were measured. For evaluation of neuroprotective effects, formation of polyglutamine (polyQ40) clusters, α-synuclein aggregates, loss of amphid sensilla (ASH) neuronal function, and amyloid β (Aβ) accumulation (as markers for Huntington's, Parkinson's, and Alzheimer's) was examined.

RESULTS: The extract, which contains substantial amounts of phenolic phytochemicals, showed an increase in the survival rate of worms challenged with juglone in daf-16 mutants but not in skn-1 mutants. The transcription factor SKN-1 was activated by the extract, while DAF-16 was not affected. Upon application of the extract, a significant decline in GST-4 levels, polyQ40 cluster formation, number of lost ASH sensory neurons, α-synuclein aggregation, and paralysis resulting from Aβ accumulation was observed.

CONCLUSIONS: Styphnolobium japonicum fruit extract activated the SKN-1/Nrf2 pathway, resulting in oxidative stress resistance. It revealed promising pharmacological activities towards treatment of Huntington's, Parkinson's, and Alzheimer's diseases. Polyphenolics from Styphnolobium japonicum may be a promising route towards treatment of CNS disorders, but need to be tested in other in vivo systems.},
}

@article {pmid37726739,
year = {2023},
author = {Petrisko, TJ and Gargus, M and Chu, SH and Selvan, P and Whiteson, KL and Tenner, AJ},
title = {Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer's mouse models.},
journal = {Journal of neuroinflammation},
volume = {20},
number = {1},
pages = {211},
pmid = {37726739},
issn = {1742-2094},
support = {T32 AG000096/NH/NIH HHS/United States ; AG060148/NH/NIH HHS/United States ; },
abstract = {The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer's disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models.},
}

@article {pmid37726351,
year = {2023},
author = {Rahmani, A and Khamutian, S and Doosti-Irani, A and Shokoohizadeh, MJ and Shirmohammadi-Khorram, N and Sahraeei, F and Khodabakhshi, M and Ahangaran, N},
title = {The association of arsenic exposure with mortality due to cancer, diabetes, Alzheimer's and congenital anomalies using Poisson regression.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {15456},
pmid = {37726351},
issn = {2045-2322},
support = {140009308064//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
abstract = {The present study aims to determine the relationship between the concentration of arsenic in the groundwater of Hamadan province and the mortality rate due to various types of malignancies, congenital anomalies, diabetes mellitus and Alzheimer's. Mortality data due to various causes of death in Hamadan province were collected for five years (2016-2020). Sampling of drinking water was determined in the reference laboratory using polarography method. Poisson regression was used to investigate the relationship between arsenic level and the death rate due to various types of disease, at a significant level (p value < 0.05). According to the results of Poisson regression, among the various causes of death (N = 8042), Alzheimer's 5.94 (3.67-9.61), diabetes mellitus 4.05 (3.5-5.37), congenital malformations 2.98 (1.88-4.72), breast cancer 2.72 (1.56-4.71), leukemia 1.90 (1.24-2.92), stomach cancer 1.64 (1.28-2.10), Liver cancer 1.58 (1.58-2.30), other digestive organs 5.86 (3.38-10.16), meninges and brain cancer 1.57 (1.02-2.41) showed the highest relationship with arsenic contamination. The results of this study could be evidence for a positive and significant relationship between arsenic concentrations and mortality rates due to cancers, diabetes mellitus, Alzheimer disease, and congenital malformations. Therefore, it's necessary to use appropriate water treatment methods to remove arsenic at the source in contaminated areas.},
}

@article {pmid37725199,
year = {2023},
author = {Dave, BP and Shah, YB and Maheshwari, KG and Mansuri, KA and Prajapati, BS and Postwala, HI and Chorawala, MR},
title = {Pathophysiological Aspects and Therapeutic Armamentarium of Alzheimer's Disease: Recent Trends and Future Development.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {37725199},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more.},
}

@article {pmid37725102,
year = {2023},
author = {Han, YH and Liu, XD and Jin, MH and Sun, HN and Kwon, T},
title = {Role of NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {},
number = {},
pages = {},
pmid = {37725102},
issn = {1420-908X},
support = {KGM5162322//KRIBB Research Initiative Program/ ; },
abstract = {BACKGROUND: Neurodegenerative diseases are a common group of neurological disorders characterized by progressive loss of neuronal structure and function leading to cognitive impairment. Recent studies have shown that neuronal pyroptosis mediated by the NLRP3 inflammasome plays a crucial role in the pathogenesis of neurodegenerative diseases.

OBJECTIVE AND METHOD: The NLRP3 inflammasome is a multiprotein complex that, when activated within cells, triggers an inflammatory response, ultimately leading to pyroptotic cell death of neurons. Pyroptosis is a typical pro-inflammatory programmed cell death process occurring downstream of NLRP3 inflammasome activation, characterized by the formation of pores on the cell membrane by the GSDMD protein, leading to cell lysis and the release of inflammatory factors. It has been found that NLRP3 inflammasome-mediated neuronal pyroptosis is closely associated with the development of various neurodegenerative diseases, such as Alzheimer's disease, traumatic brain injury, and Parkinson's disease. Therefore, inhibiting NLRP3 inflammasome activation and attenuating neuronal pyroptosis could potentially serve as novel strategies for the treatment of neurodegenerative diseases.

RESULTS: The aim of this review is to explore the role of NLRP3 activation-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases. Firstly, we extensively discuss the relationship between NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in various neurodegenerative diseases. Subsequently, we further explore the mechanisms driving NLRP3 activation and assembly, as well as the post-translational modifications regulating NLRP3 inflammasome activation.

CONCLUSION: Understanding these mechanisms will contribute to a deeper understanding of the link between neuronal pyroptosis and neurodegenerative diseases, and hold significant implications for the treatment and prevention of neurodegenerative diseases.},
}

@article {pmid37724238,
year = {2023},
author = {Sontakke, MG and Sontakke, NG and Parihar, AS},
title = {Fluid Resuscitation in Patients With Traumatic Brain Injury: A Comprehensive Review.},
journal = {Cureus},
volume = {15},
number = {8},
pages = {e43680},
pmid = {37724238},
issn = {2168-8184},
abstract = {Patients with traumatic brain injury (TBI) or head trauma present challenges for emergency physicians and neurosurgeons. Traumatic brain injury is currently a community health issue. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. The initial rapid infusion of large volumes of mannitol and a hypertonic crystalloid solution to restore blood pressure and blood volume is the current standard of care for people with combined hemorrhagic shock (HS) and traumatic brain injury. The selection and administration of fluids to trauma and traumatic brain injury patients may be especially helpful in preventing subsequent ischemic brain damage because of the hemodynamic stabilizing effects of these fluids in hypovolemic shock. Traumatic brain injury is an essential factor that may lead to disability and death in a patient. Traumatic brain damage can develop either as a direct result of the trauma or as a result of the initial harm. Significant neurologic problems, such as cranial nerve damage, dementia, seizures, and Alzheimer's disease, can develop after a traumatic brain injury. The comorbidity of the victims may also be significantly increased by additional psychiatric problems such as psychological diseases and other behavioral and cognitive sequels. We review the history of modern fluid therapy, complications after traumatic brain injury, and the use of fluid treatment for decompressive craniectomy and traumatic brain injury.},
}

@article {pmid37723924,
year = {2023},
author = {Conger, N and Osmaniye, D and Sağlık, BN and Levent, S and Ozkay, Y and Kaplancıklı, ZA},
title = {Design, synthesis, biological activities, and evaluation of molecular docking-dynamics studies of new thiosemicarbazones that may be effective against Alzheimer's disease.},
journal = {Journal of molecular recognition : JMR},
volume = {},
number = {},
pages = {e3059},
doi = {10.1002/jmr.3059},
pmid = {37723924},
issn = {1099-1352},
abstract = {Donepezil is one of the most used drugs in the treatment of Alzheimer's disease. Its activity as an AChE inhibitor makes new studies with these enzyme inhibitors attractive. For this purpose, in this study, 12 compounds including thiosemicarbazone pharmacophore, have been synthesized for the treatment of the Alzheimer's disease. 3,4-Dimethoxybenzene or 1,3-benzodioxolone rings were used for the PAS region. The substituted piperazine benzene structure is preferred for the CAS region. At the same time, the thiosemicarbazone pharmacophore structure with known ChE enzyme inhibition potential was used as a bridge connecting the CAS and PAS regions. Structure determination of compounds 3a-3l were revealed using [13] C-NMR, [1] H-NMR, and HRMS spectroscopic methods. The inhibition profile of obtained compounds (3a-3l) against ChE was evaluated using in vitro modified Ellman method. Compounds 3a, 3b, 3f, 3g and 3i exhibited inhibitory activity against the AChE enzyme. Compound 3a showed the highest inhibitory potential with an IC50 = 0.030 ± 0.001 μM. As a result of molecular docking studies, compound 3a displayed important interactions compared to other active derivatives. Molecular dynamics studies are important to see the stability of the complex formed by ligand and protein. RMSD, RMSF ang Rg parameters were calculated via dynamic studies. In conclusion, compound 3a may be a potential AChE enzyme inhibitor with its strong inhibitory potential and behavior in silico.},
}