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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 04 Mar 2024 at 01:37 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: ( alzheimer*[TIAB] AND treatment[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2024-03-01

Culibrk RA, Ebbert KA, Yeisley DJ, et al (2024)

Impact of Suramin on Key Pathological Features of Sporadic Alzheimer's Disease-Derived Forebrain Neurons.

Journal of Alzheimer's disease : JAD pii:JAD230600 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter "autophagy"). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology.

OBJECTIVE: In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons.

METHODS: Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density.

RESULTS: Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment.

CONCLUSIONS: These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy.

RevDate: 2024-03-01

Verwaerde P, Estrella C, Burlet S, et al (2024)

First-In-Human Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of AZP2006, A Synthetic Compound for the Treatment of Alzheimer's Disease and Related Diseases.

Journal of Alzheimer's disease : JAD pii:JAD220883 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are major neurodegenerative conditions with tau pathology in common but distinct symptoms-AD involves cognitive decline while PSP affects balance and eye movement. Progranulin (PGRN) is a growth factor implicated in neurodegenerative diseases, including AD and PSP. AZP2006, a synthetic compound, targets tauopathies by stabilizing PGRN levels and reducing tau aggregation and neuroinflammation.

OBJECTIVE: Evaluate the safety, tolerability, and pharmacokinetics of AZP2006.

METHODS: A first-in-Human phase 1 study comprised a single ascending dose (SAD) and a multiple ascending dose study (MAD). The SAD study included 64 healthy male volunteers and tested singles oral doses of 3 to 500 mg of AZP2006 free base equivalent or placebo. In the MAD study, 24 healthy male volunteers were administered oral doses of 30, 60, and 120 mg per day of AZP2006 or placebo for 10 days.

RESULTS: No serious adverse events were observed. Clinical, biological, and electrocardiogram findings were non-relevant. Nineteen minor adverse events resolved before study completion. The safety profile indicated no specific risks. The multiple ascending dose study was halted, and the optional dose level of 180 mg was not performed due to high levels of M2 metabolite in plasma that necessitated additional preclinical evaluation of M2. Both AZP2006 and its M2 metabolite were quickly absorbed and widely distributed in tissues. Exposure increased more than proportionally with dose.

CONCLUSIONS: AZP2006 had a favorable safety profile and was rapidly absorbed. Elevated M2 metabolite levels necessitated further studies to clarify excretion and metabolism mechanisms.

RevDate: 2024-03-01

Mathew B, Oh JM, Parambi DGT, et al (2024)

Enzyme Inhibition Assays for Monoamine Oxidase.

Methods in molecular biology (Clifton, N.J.), 2761:329-336.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines with two isoforms, namely, MAO-A and MAO-B, in mitochondrial outer membranes. These two types of MAO-A and MAO-B participate in changes in levels of neurotransmitter such as serotonin (5-hydroxytryptamine) and dopamine. Selective MAO-A inhibitors have been targeted for anti-depression treatment, while selective MAO-B inhibitors are targets of therapeutic agents for Alzheimer's disease and Parkinson's disease. For this reason, study on the development of MAO inhibitors has recently become important. Here, we describe methods of MAO activity assay, especially continuous spectrophotometric methods, which give relatively high accuracy. MAO-A and MAO-B can be assayed using kynuramine and benzylamine as substrates, respectively, at 316 nm and 250 nm, respectively, to measure their respective products, 4-hydroxyquinoline and benzaldehyde. Inhibition degree and pattern can be analyzed by using the Lineweaver-Burk and secondary plots in the presence of inhibitor, and reversibility of inhibitor can be determined by using the dialysis method.

RevDate: 2024-03-01

Iqbal S, D Pal (2024)

microRNA Isolation, Expression Profiling, and Target Identification for Neuroprotection in Alzheimer's Disease.

Methods in molecular biology (Clifton, N.J.), 2761:277-290.

Millions of people throughout the world are affected by neurodegenerative disorders like Alzheimer's disease (AD), making them a major public health concern. To create successful medicines, early diagnosis and illness monitoring are required. Emerging as possible diagnostic and treatment tools for neurodegenerative illnesses are biomarkers such as microRNAs (miRNAs). In the realm of neuroscience, miRNAs have been discovered to function as essential regulators of gene expression, with roles spanning development, differentiation, and illness. Several neurodegenerative diseases, including AD, have been linked to miRNA dysregulation. As high-throughput methods have been developed for monitoring miRNA expression and identifying miRNA targets, miRNAs have become a prime candidate for use in diagnostics and therapy. The techniques for isolating miRNAs and the most up-to-date computational methods for finding miRNA target transcripts are both described in this chapter. This chapter will be a helpful reference for anyone investigating the role of miRNAs in AD and related neurodegenerative illnesses.

RevDate: 2024-03-01

Biswas P, SS More (2024)

Using Small Molecules for Targeting Heavy Metals in Neurotoxicity and Neuroinflammation.

Methods in molecular biology (Clifton, N.J.), 2761:135-148.

Pharmaceutical drugs, natural toxins, industrial chemicals, and various environmental toxins negatively impact the nervous system. A significant cause of many neurodegenerative diseases is neurotoxicity. Although trace amounts of heavy metals are required for the proper functioning of several metabolic pathways, their dysregulation can cause many cellular and molecular alterations, which can enhance the risks associated with several neurodegenerative diseases. For example, high levels of heavy metals like manganese (Mn) affect the central nervous system with implications in both higher-order cognitive and motor functions. In addition, the buildup of amyloid aggregates and metal ions in the brain of patients with Alzheimer's disease is associated with disease pathogenesis. Small molecules capable of targeting neuroinflammation and neuroprotection pathways would be valuable to elucidate the pathological pathways associated with metal toxicity in neurogenerative disease. This chapter will summarize the necessary steps involved in (1) culturing of cell lines and maintenance of animal models, (2) design and preparation of samples of small molecules and treatment methodologies, (3) RNA and protein isolation and preparation of tissue and cell culture samples for quantitative studies, and (4) quantitative estimation of cellular products.

RevDate: 2024-03-01

Sheikh-Bahaei N (2024)

Magnetic Resonance Spectroscopy (MRS) in Alzheimer's Disease.

Methods in molecular biology (Clifton, N.J.), 2785:115-142.

MRS is a noninvasive technique to measure different metabolites in the brain. Changes in the levels of certain metabolites can be used as surrogate markers for Alzheimer's disease. They can potentially be used for diagnosis, prediction of prognosis, or even assessing response to treatment.There are different techniques for MRS acquisitions including STimulated Echo Acquisition Mode (STEAM) and Point Resolved Spectroscopy (PRESS). In terms of localization, single or multi-voxel methods can be used. Based on current data: 1. NAA, marker of neuronal integrity and viability, reduces in AD with longitudinal changes over the time as the disease progresses. There are data claiming that reduction of NAA is associated with tau accumulation, early neurodegenerative processes, and cognitive decline. Therefore, it can be used as a stage biomarker for AD to assess the severity of the disease. With advancement of disease modifying therapies, there is a potential role for NAA in the future to be used as a marker of response to treatment. 2. mI, marker of glial cell proliferation and activation, is associated with AB pathology and has early changes in the course of the disease. The NAA/mI ratio can be predictive of AD development with high specificity and can be utilized in the clinical setting to stratify cases for further evaluation with PET for potential treatments. 3. The changes in the level of other metabolites such as Chol, Glu, Gln, and GABA are controversial because of the lack of standardization of MRS techniques, current technical limitations, and possible region specific changes. 4. Ultrahigh field MRS and more advanced techniques can overcome many of these limitations and enable us to measure more metabolites with higher accuracy. 5. Standardization of MRS techniques, validation of metabolites' changes against PET using PET-guided technique, and longitudinal follow-ups to investigate the temporal changes of the metabolites in relation to other biomarkers and cognition will be crucial to confirm the utility of MRS as a potential noninvasive biomarker for AD.

RevDate: 2024-03-01

Perneczky R (2024)

Alzheimer's Disease Prevention and Treatment Based on Population-Based Approaches.

Methods in molecular biology (Clifton, N.J.), 2785:15-33.

The development of effective prevention and treatment strategies for Alzheimer's disease (AD) and dementia is hindered by limited knowledge of the underlying biological and environmental causes. While certain genetic factors have been associated with AD, and various lifestyle and environmental factors have been linked to dementia risk, the interactions between genes and the environment are not yet fully understood. To identify new avenues for dementia prevention, coordinated global efforts are needed to utilize existing cohorts and resources effectively and efficiently. This chapter provides an overview of current research on risk and protective factors for AD and dementia and discusses the opportunities and challenges associated with population-based approaches.

RevDate: 2024-03-01

Perneczky R, Hansen N, Hofmann A, et al (2024)

Blood-Based Biomarkers for Early Alzheimer's Disease Diagnosis in Real-World Settings.

Methods in molecular biology (Clifton, N.J.), 2785:3-14.

As our knowledge about the biology of Alzheimer's disease (AD) expands and we recognize the significance of early intervention for effective treatment, there is a shift in focus toward detecting the disease at an early stage. AD is characterized by the accumulation of misfolded amyloid-β (Aβ) and phosphorylated tau proteins in the brain, leading to the formation of senile plaques and neurofibrillary tangles. While a definitive diagnosis of AD can only be confirmed through autopsy by examining these pathological features, there are now reliable methods available for diagnosing the disease in living individuals. These methods involve analyzing cerebrospinal fluid and using positron emission tomography to accurately assess the presence of Aβ and tau proteins. While these diagnostic markers have shown high accuracy in memory-clinic populations, they do have limitations such as the requirement for invasive lumbar puncture or exposure to ionizing radiation. Additionally, they are not easily accessible outside of specialized healthcare settings. Blood-based biomarkers of the core pathological features of AD are being developed, showing promise for less invasive, scalable identification of AD cases in the community. The advantages for the healthcare systems of this development are obvious, but the diagnostic performance of blood-based biomarkers in broader, non-selected populations outside of retrospective analyses and research cohorts still requires further investigation, including the combination with more effective neuropsychological assessments such as digital cognitive test solutions.

RevDate: 2024-03-01

Brigo F, S Lattanzi (2024)

Diagnosing epileptic seizures in patients with Alzheimer's disease and deciding on the appropriate treatment plan.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is the predominant cause of dementia and a significant contributor to morbidity among the elderly. Patients diagnosed with AD face an increased risk of epileptic seizures.

AREAS COVERED: Herein, the authors review the challenges in the diagnosis of seizures in patients with AD, the risks of seizures related to medications used in AD and the pharmacological treatment of seizures in AD. The authors also provide the reader with their expert opinion on the subject matter and future perspectives.

EXPERT OPINION: Healthcare professionals should maintain a vigilant approach to suspecting seizures in AD patients. Acute symptomatic seizures triggered by metabolic disturbances, infections, toxins, or drug-related factors often have a low risk of recurrence. In such cases, addressing the underlying cause may suffice without initiating antiseizure medications (ASMs). However, unprovoked seizures in certain AD patients carry a higher risk of recurrence over time, warranting the use of ASMs. Although data is limited, both lamotrigine and levetiracetam appear to be reasonable choices for controlling seizures in elderly AD patients. Decisions should be informed by the best available evidence, the treating physician's clinical experience, and the patient's preferences.

RevDate: 2024-03-02

Amini R, Moradi S, Najafi R, et al (2024)

BACE1 Inhibition Utilizing Organic Compounds Holds Promise as a Potential Treatment for Alzheimer's and Parkinson's Diseases.

Oxidative medicine and cellular longevity, 2024:6654606.

BACKGROUND: Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1).

OBJECTIVES: In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates.

METHODS: This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations.

RESULTS: Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable.

CONCLUSION: The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors.

RevDate: 2024-03-02

Zhang W, Gan B, Wang T, et al (2023)

Extracellular vesicles in the treatment of oxidative stress injury: global research status and trends.

Frontiers in molecular biosciences, 10:1273113.

Objective: The aim of this study was to conduct a bibliometric analysis of the literature on "Extracellular Vesicles in the Treatment of Oxidative Stress Injury" and to reveal its current status, hot spots and trends. Methods: The relevant literature was obtained from the Web of Science Core Collection (WoSCC) on 29 April 2023. We performed clustering and partnership analysis of authors, institutions, countries, references and keywords in the literature through CiteSpace software and the bibliometric online analysis platform and mapped the relevant knowledge maps. Results: A total of 1,321 relevant publications were included in the bibliometric analysis, with the number of publications in this field increasing year by year. These included 944 "articles" and 377 "reviews". The maximum number of publications published in China is 512, and the maximum number of highly cited publications published in the United States is 20. Based on CiteSpace, the country collaboration network map shows close and stable collaboration among high-productivity countries. Based on WoSCC, there are 1706 relevant research institutions and 119 highly cited elite institutions, among which Kaohsing Chang Gung Men Hosp has the most extensive influence. Studies related to "Extracellular Vesicles in the Treatment of Oxidative Stress Injury" have been published in 548 journals. The keywords of the publications show the main research areas and breakthroughs. Based on WoSCC, the keywords of the research area "Extracellular Vesicles in the Treatment of Oxidative Stress Injury" were found to be as follows: exosome(s), extracellular vesicle(s), oxidative stress, inflammation, mesenchymal stem cells, apoptosis, microRNA (miRNA), mitochondria, biomarker, autophagy, angiogenesis and Alzheimer's disease. Analysis showed that "mesenchymal stem cells", "microRNA", "autophagy", "histology" and "therapeutic" emerged as highly explosive keywords. Conclusion: This study is the first to use visual software and data mining to assess the literature in the field of "Extracellular Vesicles in the Treatment of Oxidative Stress Injury". The research history, research status and direction in this field provide a theoretical basis for its scientific research.

RevDate: 2024-03-01

Tekade A, Kadam P, Jagdale S, et al (2024)

Exploring Potential of Nano-formulations in the Treatment of Alzheimer's Disease through Nasal Route.

Current Alzheimer research pii:CAR-EPUB-138873 [Epub ahead of print].

OBJECTIVE: Alzheimer's disease, a progressive neurodegenerative disorder, severely impacts cognitive function and daily living. The current treatment provides only symptomatic relief, and thus, disease-modifying therapies targeting underlying causes are needed. Although several potential therapies are in various stages of clinical trials, bringing a new Alzheimer's drug to market remains challenging. Hence, researchers are also exploring monoclonal antibodies, tau protein inhibitors, and anti-inflammatory drugs as treatment options. Conventionally designed dosage forms come with limitations like poor absorption, first-pass metabolism, and low bioavailability. They also cause systemic adverse effects because these designed systems do not provide target- specific drug delivery. Thus, in this review, the authors highlighted the current advancements in the development of intranasal nanoformulations for the treatment of Alzheimer's disease. This strategy of delivering anti-Alzheimer drugs through the nasal route may help to target the drug exactly to the brain, achieve rapid onset of action, avoid first-pass metabolism, and reduce the side effects and dose required for administration.

CONCLUSION: Delivering drugs to the brain through the nasal route for treating Alzheimer's disease is crucial due to the limited efficacy of existing treatments and the profound impact of the disease on patients and their families. Thus, by exploring innovative approaches such as nose-to-brain drug delivery, it is possible to improve the quality of life for individuals living with Alzheimer's and alleviate its societal burden.

RevDate: 2024-02-29

Jönsson L, Ivkovic M, Atri A, et al (2024)

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer's disease.

Alzheimer's research & therapy, 16(1):48.

BACKGROUND: The clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer's disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes.

METHODS: We simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale-sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer's Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years.

RESULTS: The PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease.

CONCLUSION: PMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

RevDate: 2024-02-29

Mary A, Mancuso R, MT Heneka (2024)

Immune Activation in Alzheimer Disease.

Annual review of immunology [Epub ahead of print].

Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, and economic burdens are expected to dramatically increase. AD is historically characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles, but over the last 25 years chronic immune activation has been identified as an important factor contributing to AD pathogenesis. In this article, we review recent and important advances in our understanding of the significance of immune activation in the development of AD. We describe how brain-resident macrophages, the microglia, are able to detect Aβ species and be activated, as well as the consequences of activated microglia in AD pathogenesis. We discuss transcriptional changes of microglia in AD, their unique heterogeneity in humans, and emerging strategies to study human microglia. Finally, we expose, beyond Aβ and microglia, the role of peripheral signals and different cell types in immune activation. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2024-02-29

Korczyn AD, LT Grinberg (2024)

Is Alzheimer disease a disease?.

Nature reviews. Neurology [Epub ahead of print].

Dementia, a prevalent condition among older individuals, has profound societal implications. Extensive research has resulted in no cure for what is perceived as the most common dementing illness: Alzheimer disease (AD). AD is defined by specific brain abnormalities - amyloid-β plaques and tau protein neurofibrillary tangles - that are proposed to actively influence the neurodegenerative process. However, conclusive evidence of amyloid-β toxicity is lacking, the mechanisms leading to the accumulation of plaques and tangles are unknown, and removing amyloid-β has not halted neurodegeneration. So, the question remains, are we making progress towards a solution? The complexity of AD is underscored by numerous genetic and environmental risk factors, and diverse clinical presentations, suggesting that AD is more akin to a syndrome than to a traditional disease, with its pathological manifestation representing a convergence of pathogenic pathways. Therefore, a solution requires a multifaceted approach over a single 'silver bullet'. Improved recognition and classification of conditions that converge in plaques and tangle accumulation and their treatment requires the use of multiple strategies simultaneously.

RevDate: 2024-02-29

Madar P, Nagalapur P, Chaudhari S, et al (2024)

The Unveiling of Therapeutic Targets for Alzheimer's Disease: An Integrative Review.

Current topics in medicinal chemistry pii:CTMC-EPUB-138853 [Epub ahead of print].

Alzheimer's disease (AD) is characterized by a complex pathological landscape, necessitating a comprehensive treatment approach. This concise review paper delves into the idea of addressing multiple mechanisms in AD, summarizing the latest research findings on pathogenesis, risk factors, diagnostics, and therapeutic strategies. The etiology of AD is multifaceted, involving genetic, environmental, and lifestyle factors. The primary feature is the accumulation of amyloid-- beta and tau proteins, leading to neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal loss. Conventional single-target therapies have shown limited effectiveness, prompting a shift toward simultaneously addressing multiple disease-related processes. Recent advancements in AD research underscore the potential of multifaceted therapies. This review explores strategies targeting both tau aggregation and amyloid-beta, along with interventions to alleviate neuroinflammation, enhance synaptic function, and reduce oxidative stress. In conclusion, the review emphasizes the growing importance of addressing various pathways in AD treatment. A holistic approach that targets different aspects of the disease holds promise for developing effective treatments and improving the quality of life for Alzheimer's patients and their caregivers.

RevDate: 2024-02-29

Kim S, Shin SJ, Nam Y, et al (2024)

Korean red ginseng polysaccharide as a potential therapeutic agent targeting tau pathology in Alzheimer's disease.

International journal of biological macromolecules pii:S0141-8130(24)01319-9 [Epub ahead of print].

Tau is a microtubule-associated protein that plays a critical role in the stabilization and modulation of neuronal axons. Tau pathology is stronger associated with cognitive decline in patients with Alzheimer's disease (AD) than amyloid beta (Aβ) pathology. Hence, tau targeting is a promising approach for the treatment of AD. Previous studies have demonstrated that the non-saponin fraction with rich polysaccharide (NFP) from Korean red ginseng (KRG) can modulate tau aggregation and exert a therapeutic effect on AD. Therefore, we investigated the efficacy of NFP isolated from KRG on tau pathology in experimental models of AD. Our results showed that NFP from KRG ameliorated deposition and hyperphosphorylation of tau in the brain of 3xTg mice. Moreover, NFP from KRG modulated the aggregation and dissociation of tau K18 in vitro. We demonstrated the alleviatory effects of NFP from KRG on hyperphosphorylated tau and tau kinase in okadaic acid-treated HT22 cells. Furthermore, NFP from KRG mitigated Aβ deposition, neurodegeneration, and neuroinflammation in 3xTg mice. We revealed the neuroprotective effects of NFP from KRG on tau-induced neuronal loss in HT22 cells. Our results indicate that NFP extracted from KRG is a novel therapeutic agent for the treatment of AD associated with tau pathology.

RevDate: 2024-02-29

Song C, Chu Z, Dai J, et al (2024)

Water extract of moschus alleviates erastin-induced ferroptosis by regulating the Keap1/Nrf2 pathway in HT22 cells.

Journal of ethnopharmacology pii:S0378-8741(24)00236-8 [Epub ahead of print].

Moschus, first described in the Shennong's Classic of the Materia medicine, is a scarce and precious animal medicine. Modern pharmacological researches have suggested that Moschus has neuroprotective actions, and its mechanism is related to anti-inflammatory, antioxidant, and anti-apoptosis effects. Ferroptosis is one of the major pathologies of Alzheimer's disease (AD) and is widely implicated in the pathogenesis and progression of AD. Although previous studies have suggested that Moschus possesses neuroprotective effect, whether Moschus could mitigate neuronal damages by inhibiting the onset of ferroptosis is unknown in model cells of AD.

AIM OF THE STUDY: The aim of study was to explore the water extract of Moschus (WEM) on ferroptosis caused by erastin and the potential mechanism.

MATERIALS AND METHODS: Erastin was used to stimulate HT22 cells to form ferroptosis model to evaluate the anti-ferroptosis effect of WEM by cell counting kit-8 and lactic dehydrogenase tests. The malondialdehyde (MDA) and glutathione (GSH) kits are used for detection of MDA and GSH levels, and 2',7'-dichlorofluorescein diacetate and C11 BODIPY 581/591 fluorescence probe are used for evaluation of reactive oxygen species (ROS) and lipid peroxide (LOOH) levels. And Western blot was used to test nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), and ferroptosis associated proteins including glutathione peroxidase 4 (GPX4), cystine/glutamate antiporter subunit (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin1 (FPN1), transferrin receptor (TFRC). In addition, the Nrf2 inhibitor ML385 was applied to verify whether WEM prevents erastin-induced ferroptosis by activating the Keap1/Nrf2 pathway.

RESULTS: After WEM treatment, erastin-induced HT22 cell survival was significantly elevated, the accumulation of intracellular MDA, ROS, and LOOH were significantly reduced, the level of GSH and expressions of ferroptosis inhibitors GPX4 and SLC7A11 were significantly increased, and iron metabolism-related proteins TFRC, FPN1, and FTH1 were regulated. These effects of WEM are implemented by activating the Keap1/Nrf2 pathway.

CONCLUSIONS: This study demonstrated that WEM could perform neuroprotective effects by alleviating ferroptosis, verified that WEM treatment of AD can be mediated by the Keap1/Nrf2 pathway, and provided theoretical support for the application of WEM in the treatment of AD.

RevDate: 2024-02-29

Lu H, Ran S, Zhang Y, et al (2024)

Neuroprotective effects of Shenghui decoction via inhibition of the JNK/p38 MAPK signaling pathway in an AlCl3-induced zebrafish (Danio rerio) model of Alzheimer's disease.

Journal of ethnopharmacology pii:S0378-8741(24)00292-7 [Epub ahead of print].

Alzheimer's disease (AD) is a multi-factorial degenerative disease, and multi-targeted therapies targeting multiple pathogenic mechanisms should be explored. Shenghui decoction (SHD) is an ancient traditional Chinese medicine (TCM) formula used clinically to alleviate AD. However, the precise mechanism of action of SHD as a therapeutic agent for AD remains unclear.

AIM OF THE STUDY: This study investigated the neuroprotective properties and potential mechanisms of action of SHD in mitigating AD-like symptoms induced by AlCl3 in a zebrafish model.

MATERIALS AND METHODS: Active components of SHD were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Zebrafish were exposed to AlCl3 (200 μg/L) for 30 days to establish an AD zebrafish model. AlCl3-exposed zebrafish were treated with SHD or donepezil. Behavioral tests were used to assess learning and memory, locomotor activity, and AD-related anxiety and aggression in AlCl3-exposed zebrafish. Nissl staining and transmission electron microscopy were used to evaluate histological alterations in brain neurons. The concentrations of pro-inflammatory cytokines (tumor necrosis factor-α, TNF-α; interleukin-1β, IL-1β) were quantified using Enzyme-linked immunosorbent assay (ELISA). Markers of oxidative stress and cholinergic activity (acetylcholinesterase, AChE) were detected using biochemical assays. Western blotting and immunofluorescence were used to detect the protein expression levels of Aβ, p-tau, PSD-95, synaptophysin, TLR4, phosphorylation of NF-κB p65, p38, and JNK.

RESULTS: Fifteen SHD compounds were identified by UPLC-MS/MS analysis. SHD improved AlCl3-induced dyskinesia, learning and memory impairment, anxiety-like behavior, and aggressive behavior in zebrafish. AlCl3-exposed zebrafish showed AD-like pathology, overexpression of Aβ, hyperphosphorylated tau protein, marked neuronal damage, decreased expression of synaptic proteins, synaptophysin, and PSD-95, and impairment of synaptic structural plasticity. These effects were reversed by the SHD treatment. We also observed that SHD ameliorated oxidative stress and decreased AChE activity and inflammatory cytokine levels. These effects are similar to those observed for donepezil. Meanwhile, SHD could decrease the protein expression of TLR4 and inhibit phosphorylation of NF-κB, JNK, and p38 MAPK. These results demonstrate that SHD has the potential to exert neuroprotective effects, which may be partly mediated via inhibition of the JNK/p38 MAPK signaling pathway.

CONCLUSIONS: Our findings revealed the therapeutic mechanism of SHD in mitigating AD progression and suggested that SHD is a potent neuroprotectant that contributes to the future development of TCM modernization and broader clinical applications.

RevDate: 2024-02-29

van Gils V, Rizzo M, Côte J, et al (2024)

The association of glucose metabolism measures and diabetes status with Alzheimer's disease biomarkers of amyloid and tau: a systematic review and meta-analysis.

Neuroscience and biobehavioral reviews pii:S0149-7634(24)00073-3 [Epub ahead of print].

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated haemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-β and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03-0.18], p=0.008; I2=68%), but were not associated with amyloid-β biomarkers (r=-0.06[-0.13-0.01], p=0.08; I[2]=81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-β biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-β. This knowledge is valuable for improving dementia and DM diagnostics and treatment.

RevDate: 2024-02-29

Xu M, Lin R, Wen H, et al (2024)

Electroacupuncture Enhances the Functional Connectivity of Limbic System to Neocortex in the 5xFAD Mouse Model of Alzheimer's Disease.

Neuroscience pii:S0306-4522(24)00090-3 [Epub ahead of print].

Our previous study revealed that acupuncture may exhibit therapeutic effects on Alzheimer's disease (AD) through the activation of metabolism in memory-related brain regions. However, the underlying functional mechanism remains poorly understood and warrants further investigation. In this study, we used resting-state functional magnetic resonance imaging (rsfMRI) to explore the potential effect of electroacupuncture (EA) on the 5xFAD mouse model of AD. We found that the EA group exhibited significant improvements in the number of platforms crossed and the time spent in the target quadrant when compared with the model group (p<0.05). The functional connectivity (FC) of left hippocampus (Hip) was enhanced significantly among 12 regions of interest (ROIs) in the EA group (p<0.05). Based on the left Hip as the seed point, the rsfMRI analysis of the entire brain revealed increased FC between the limbic system and the neocortex in the 5xFAD mice after EA treatment. Additionally, the expression of Aβ protein and deposition in the Hip showed a downward trend in the EA group compared to the model group (p<0.05). In conclusion, our findings indicate that EA treatment can improve the learning and memory abilities and inhibit the expression of Aβ protein and deposition of 5xFAD mice. This improvement may be attributed to the enhancement of the resting-state functional activity and connectivity within the limbic-neocortical neural circuit, which are crucial for cognition, motor function, as well as spatial learning and memory abilities in AD mice.

RevDate: 2024-03-01
CmpDate: 2024-03-01

Zhao T, J Jia (2024)

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

CNS neuroscience & therapeutics, 30(2):e14581.

AIMS: We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD).

METHODS: The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aβ42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis.

RESULTS: We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. In vivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. In vitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both in vivo and in vitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway.

CONCLUSIONS: PA is expected to provide a valuable candidate for new drug development for AD in the future.

RevDate: 2024-03-01

Alavi MS, Al-Asady AM, Fanoudi S, et al (2024)

Differential effects of antiseizure medications on neurogenesis: Evidence from cells to animals.

Heliyon, 10(4):e26650.

Neurogenesis, the process of generating functionally integrated neurons from neural stem and progenitor cells, is involved in brain development during embryonic stages but continues throughout life. Adult neurogenesis plays essential roles in many brain functions such as cognition, brain plasticity, and repair. Abnormalities in neurogenesis have been described in many neuropsychiatric and neurological disorders, including epilepsy. While sharing a common property of suppressing seizures, accumulating evidence has shown that some antiseizure medications (ASM) exhibit neuroprotective potential in the non-epileptic models including Parkinson's disease, Alzheimer's disease, cerebral ischemia, or traumatic brain injury. ASM are a heterogeneous group of medications with different mechanisms of actions. Therefore, it remains to be revealed whether neurogenesis is a class effect or related to them all. In this comprehensive literature study, we reviewed the literature data on the influence of ASM on the neurogenesis process during brain development and also in the adult brain under physiological or pathological conditions. Meanwhile, we discussed the underlying mechanisms associated with the neurogenic effects of ASM by linking the reported in vivo and in vitro studies. PubMed, Web of Science, and Google Scholar databases were searched until the end of February 2023. A total of 83 studies were used finally. ASM can modulate neurogenesis through the increase or decrease of proliferation, survival, and differentiation of the quiescent NSC pool. The present article indicated that the neurogenic potential of ASM depends on the administered dose, treatment period, temporal administration of the drug, and normal or disease context.

RevDate: 2024-03-01
CmpDate: 2024-03-01

Kim BJ, Bak SB, Bae SJ, et al (2024)

Protective Effects of Red Ginseng Against Tacrine-Induced Hepatotoxicity: An Integrated Approach with Network Pharmacology and Experimental Validation.

Drug design, development and therapy, 18:549-566.

INTRODUCTION: Tacrine, an FDA-approved acetylcholinesterase inhibitor, has shown efficacy in treating Alzheimer's disease, but its clinical use is limited by hepatotoxicity. This study investigates the protective effects of red ginseng against tacrine-induced hepatotoxicity, focusing on oxidative stress.

METHODS: A network depicting the interaction between compounds and targets was constructed for RG. Effect of RG was determined by MTT and FACS analysis with cells stained by rhodamine 123. Proteins were extracted and subjected to immunoblotting for apoptosis-related proteins.

RESULTS: The outcomes of the network analysis revealed a significant association, with 20 out of 82 identified primary RG targets aligning with those involved in oxidative liver damage including notable interactions within the AMPK pathway. in vitro experiments showed that RG, particularly at 1000μg/mL, mitigated tacrine-induced apoptosis and mitochondrial damage, while activating the LKB1-mediated AMPK pathway and Hippo-Yap signaling. In mice, RG also protected the liver injury induced by tacrine, as similar protective effects to silymarin, a well-known drug for liver toxicity protection.

DISCUSSION: Our study reveals the potential of RG in mitigating tacrine-induced hepatotoxicity, suggesting the administration of natural products like RG to reduce toxicity in Alzheimer's disease treatment.

RevDate: 2024-03-01

Xu M, Liu J, Liu Q, et al (2024)

Preliminary study on early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice using multimodal magnetic resonance imaging.

Frontiers in aging neuroscience, 16:1326394.

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and [1]H-magnetic resonance spectroscopy ([1]H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, [1]H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

RevDate: 2024-03-01
CmpDate: 2024-03-01

Rizzi L, LT Grinberg (2024)

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.

Acta neuropathologica communications, 12(1):36.

Tauopathies are neurodegenerative diseases that typically require postmortem examination for a definitive diagnosis. Detecting neurotoxic tau fragments in cerebrospinal fluid (CSF) and serum provides an opportunity for in vivo diagnosis and disease monitoring. Current assays primarily focus on total tau or phospho-tau, overlooking other post-translational modifications (PTMs). Caspase-cleaved tau is a significant component of AD neuropathological lesions, and experimental studies confirm the high neurotoxicity of these tau species. Recent evidence indicates that certain caspase-cleaved tau species, such as D13 and D402, are abundant in AD brain neurons and only show a modest degree of co-occurrence with phospho-tau, meaning caspase-truncated tau pathology is partially distinct and complementary to phospho-tau pathology. Furthermore, these caspase-cleaved tau species are nearly absent in 4-repeat tauopathies. In this review, we will discuss the significance of caspase-cleaved tau in the development of tauopathies, specifically emphasizing its role in AD. In addition, we will explore the potential of caspase-cleaved tau as a biomarker and the advantages for drug development targeting caspase-6. Developing specific and sensitive assays for caspase-cleaved tau in biofluids holds promise for improving the diagnosis and monitoring of tauopathies, providing valuable insights into disease progression and treatment efficacy.

RevDate: 2024-02-28

Chen Z, Wang X, Du S, et al (2024)

A review on traditional Chinese medicine natural products and acupuncture intervention for Alzheimer's disease based on the neuroinflammatory.

Chinese medicine, 19(1):35.

Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development. It is clinically characterized by cognitive impairment, memory impairment and behavioral change. Chinese herbal medicine and acupuncture are important components of traditional Chinese medicine (TCM), and are commonly used in clinical treatment of AD. This paper systematically summarizes the research progress of traditional Chinese medicine natural products and acupuncture treatment of AD, which combined with existing clinical and preclinical evidence, based on a comprehensive review of neuroinflammation, and discusses the efficacy and potential mechanisms of traditional Chinese medicine natural products and acupuncture treatment of AD. Resveratrol, curcumin, kaempferol and other Chinese herbal medicine components can significantly inhibit the neuroinflammation of AD in vivo and in vitro, and are candidates for the treatment of AD. Acupuncture can alleviate the memory and cognitive impairment of AD by improving neuroinflammation, synaptic plasticity, nerve cell apoptosis and reducing the production and aggregation of amyloid β protein (Aβ) in the brain. It has the characteristics of early, safe, effective and benign bidirectional adjustment. The purpose of this paper is to provide a basis for improving the clinical strategies of TCM for the treatment of AD.

RevDate: 2024-03-01

Zhang J, Song L, Miller Z, et al (2024)

Machine learning models identify predictive features of patient mortality across dementia types.

Communications medicine, 4(1):23.

BACKGROUND: Dementia care is challenging due to the divergent trajectories in disease progression and outcomes. Predictive models are needed to flag patients at risk of near-term mortality and identify factors contributing to mortality risk across different dementia types.

METHODS: Here, we developed machine-learning models predicting dementia patient mortality at four different survival thresholds using a dataset of 45,275 unique participants and 163,782 visit records from the U.S. National Alzheimer's Coordinating Center (NACC). We built multi-factorial XGBoost models using a small set of mortality predictors and conducted stratified analyses with dementiatype-specific models.

RESULTS: Our models achieved an area under the receiver operating characteristic curve (AUC-ROC) of over 0.82 utilizing nine parsimonious features for all 1-, 3-, 5-, and 10-year thresholds. The trained models mainly consisted of dementia-related predictors such as specific neuropsychological tests and were minimally affected by other age-related causes of death, e.g., stroke and cardiovascular conditions. Notably, stratified analyses revealed shared and distinct predictors of mortality across eight dementia types. Unsupervised clustering of mortality predictors grouped vascular dementia with depression and Lewy body dementia with frontotemporal lobar dementia.

CONCLUSIONS: This study demonstrates the feasibility of flagging dementia patients at risk of mortality for personalized clinical management. Parsimonious machine-learning models can be used to predict dementia patient mortality with a limited set of clinical features, and dementiatype-specific models can be applied to heterogeneous dementia patient populations.

RevDate: 2024-02-28

Ren Q, Wang S, Li J, et al (2024)

Novel social stimulation ameliorates memory deficit in Alzheimer's disease model through activating α-secretase.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.1689-23.2024 [Epub ahead of print].

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression, and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent. Additionally, we discovered that SNS caused similar changes in an AD model, FAD[4T] mice, and these alterations could be reversed by α-secretase inhibitor. Furthermore, we also found that multiple novel social (MNS) stimulation improved synaptic plasticity and memory impairments in both male and female FAD[4T] mice, accompanied by α-secretase activation and Aβ reduction. These findings provide insight into the process underpinning how social interaction helps AD patients who are experiencing cognitive decline, and we also imply that novel social interaction and activation of the α-secretase may be preventative and therapeutic in the early stages of AD.Significance Statement Alzheimer's disease is a neurodegenerative disease that endangers the health of humans all over the world, yet no effective treatment is available. Here, we propose that novel social communication is able to effectively alleviate synaptic plasticity and cognitive deficits in early AD model mice. The mechanism is related to the activation of vHPC α-secretase, which alters amyloid precursor protein (APP) cleavage pathways, leading to a decrease in Aβ generation. Our findings shed light on the underlying mechanisms by which social communication improves cognition in AD models or patients and emphasize the preventive and therapeutic potential of novel social communication and α-secretase activation in the early stages of AD.

RevDate: 2024-02-28

Kwon OB, Seo W, Kim KY, et al (2024)

The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice.

In vivo (Athens, Greece), 38(2):606-610.

BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice.

MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration.

RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101).

CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.

RevDate: 2024-02-28

Nakajima K, Han A, Kayano A, et al (2024)

Upregulation Effect of Citrus Species on Brain-Derived Neurotrophic Factor.

Journal of nutritional science and vitaminology, 70(1):61-71.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays fundamental roles in neuronal survival and synaptic plasticity. Its upregulation in the brain can effectively prevent and treat central nervous system (CNS) diseases, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD). BDNF is synthesized in various peripheral tissues as well as in the brain and can be transported from peripheral circulation into the brain through the blood-brain barrier. Therefore, foods that upregulate BDNF in peripheral tissues may be beneficial in preventing and treating these CNS diseases. Previously, we revealed that treatment with Chinpi (Citrus unshiu peel) and Citrus natsudaidai increased BDNF levels in the human renal adenocarcinoma cell line ACHN. Here, we evaluated the effects of 21 citrus cultivars on BDNF production in ACHN cells by measuring BDNF levels in the cell culture medium. We found that treatment with peels and pulps of 13 citrus varieties increased BDNF levels in ACHN cells. Treatment with Aurantium, Acrumen, and their hybrids citrus varieties showed a potent BDNF-upregulating effect but not with varieties belonging to Limonellus, Citrophorum, and Cephalocitrus. In addition, treatment with some of those Acrumen and its hybrid citrus species resulted in elevated levels of BDNF transcripts in ACHN cells. These results suggest that peels of many citrus cultivars contain ingredients with a potential BDNF-upregulating ability, which may be novel drug seeds for treating depression, AD, and PD. Furthermore, many citrus cultivars could be used as BDNF-upregulating foods.

RevDate: 2024-02-28

Mitsuishi Y, Nakano M, Kojima H, et al (2024)

Reduction of Amyloid-β Production without Inhibiting Secretase Activity by MS-275.

ACS chemical neuroscience [Epub ahead of print].

Brain amyloid-β (Aβ) governs the pathogenic process of Alzheimer's disease. Clinical trials to assess the disease-modifying effects of inhibitors or modulators of β- and γ-secretases have not shown clinical benefit and can cause serious adverse events. Previously, we found that the interleukin-like epithelial-to-mesenchymal transition inducer (ILEI, also known as FAM3C) negatively regulates the Aβ production through a decrease in Aβ immediate precursor, without the inhibition of β- and γ-secretase activity. Herein, we found that MS-275, a benzamide derivative that is known to inhibit histone deacetylases (HDACs), exhibits ILEI-like activity to reduce Aβ production independent of HDAC inhibition. Chronic MS-275 treatment decreased Aβ deposition in the cerebral cortex and hippocampus in an Alzheimer's disease mouse model. Overall, our results indicate that MS-275 is a potential therapeutic candidate for efficiently reducing brain Aβ accumulation.

RevDate: 2024-02-29

Lynch MA (2024)

A case for seeking sex-specific treatments in Alzheimer's disease.

Frontiers in aging neuroscience, 16:1346621.

There is no satisfactory explanation for the sex-related differences in the incidence of many diseases and this is also true of Alzheimer's disease (AD), where females have a higher lifetime risk of developing the disease and make up about two thirds of the AD patient population. The importance of understanding the cause(s) that account for this disproportionate distribution cannot be overestimated, and is likely to be a significant factor in the search for therapeutic strategies that will combat the disease and, furthermore, potentially point to a sex-targeted approach to treatment. This review considers the literature in the context of what is known about the impact of sex on processes targeted by drugs that are in clinical trial for AD, and existing knowledge on differing responses of males and females to these drugs. Current knowledge strongly supports the view that trials should make assessing sex-related difference in responses a priority with a focus on exploring the sex-stratified treatments.

RevDate: 2024-02-28

Doggrell SA (2024)

More failure with solanezumab - this time in preclinical Alzheimer's disease.

Expert opinion on biological therapy [Epub ahead of print].

INTRODUCTION: There is no cure for Alzheimer's disease, which is the sixth leading cause of death in the U.S.A.. Lecanemab is anti-Aβ monoclonal antibody approved for the treatment of early Alzheimer's disease but is only marginally effective. Other antibodies are being developed including solanezumab.

AREAS COVERED: A phase 3 clinical trial of solanezumab in preclinical Alzheimer's disease. In the A4 study, solanezumab did not reduce the decline in cognition or function and had no effect on brain amyloid burden.

EXPERT OPINION: After the poor results in the EXPEDITION series of trials, the development of solanezumab should have been terminated. The rationale for undertaking the A4 trial was questionable, and the lack of benefit was probable. The controversial approval of two anti-Aβ monoclonal antibodies (aducanumab, lecanemab) for the treatment of Alzheimer's disease by the US Food and Drug Administration (FDA), despite a high incidence of amyloid-related imagining abnormalities (ARIA), may be fueling this continuation of clinical development of agents such as solanezumab. The lesson from the A4 trial is that more careful/realistic consideration needs to be given before embarking on further phase 3 trials with anti-Aβ monoclonal antibodies.

RevDate: 2024-02-29
CmpDate: 2024-02-29

Ma Q, Yang F, Xiao B, et al (2024)

Emerging roles of circular RNAs in tumorigenesis, progression, and treatment of gastric cancer.

Journal of translational medicine, 22(1):207.

With an estimated one million new cases reported annually, gastric cancer (GC) ranks as the fifth most diagnosed malignancy worldwide. The early detection of GC remains a major challenge, and the prognosis worsens either when patients develop resistance to chemotherapy or radiotherapy or when the cancer metastasizes. The precise pathogenesis underlying GC is not well understood, which further complicates its treatment. Circular RNAs (circRNAs), a recently discovered class of noncoding RNAs that originate from parental genes through "back-splicing", have been shown to play a key role in various biological processes in both eukaryotes and prokaryotes. CircRNAs have been linked to cardiovascular diseases, diabetes, hypertension, Alzheimer's disease, and the occurrence and progression of tumors. Prior studies have established that circRNAs play a crucial role in GC, impacting tumorigenesis, diagnosis, progression, and therapy resistance. This review aims to summarize how circRNAs contribute to GC tumorigenesis and progression, examine their roles in the development of drug resistance, discuss their potential as biotechnological drugs, and summarize their response to therapeutic drugs and microorganism in GC.

RevDate: 2024-02-29

Taylor MK, Burns JM, Choi IY, et al (2024)

Protocol for a single-arm, pilot trial of creatine monohydrate supplementation in patients with Alzheimer's disease.

Pilot and feasibility studies, 10(1):42.

BACKGROUND: Impaired brain bioenergetics is a pathological hallmark of Alzheimer's disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition.

AIMS: The Creatine to Augment Bioenergetics in Alzheimer's disease (CABA) study is designed to primarily assess the feasibility of supplementation with 20 g/day of creatine monohydrate (CrM) in patients with cognitive impairment due to AD. Secondary aims are designed to generate preliminary data investigating changes in brain Cr levels, cognition, peripheral and brain mitochondrial function, and muscle strength and size.

METHODS: CABA is an 8-week, single-arm pilot study that will recruit 20 patients with cognitive impairment due to AD. Participants attend five in-person study visits: two visits at baseline to conduct screening and baseline assessments, a 4-week visit, and two 8-week visits. Outcomes assessment includes recruitment, retention, and compliance, cognitive testing, magnetic resonance spectroscopy of brain metabolites, platelet and lymphocyte mitochondrial function, and muscle strength and morphology at baseline and 8 weeks.

DISCUSSION: CABA is the first study to investigate CrM as a potential treatment in patients with AD. The pilot data generated by this study are pertinent to inform the design of future large-scale efficacy trials.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05383833 , registered on 20 May 2022.

RevDate: 2024-02-27

Koner S, S Luo (2024)

Projection-based two-sample inference for sparsely observed multivariate functional data.

Biostatistics (Oxford, England) pii:7615429 [Epub ahead of print].

Modern longitudinal studies collect multiple outcomes as the primary endpoints to understand the complex dynamics of the diseases. Oftentimes, especially in clinical trials, the joint variation among the multidimensional responses plays a significant role in assessing the differential characteristics between two or more groups, rather than drawing inferences based on a single outcome. We develop a projection-based two-sample significance test to identify the population-level difference between the multivariate profiles observed under a sparse longitudinal design. The methodology is built upon widely adopted multivariate functional principal component analysis to reduce the dimension of the infinite-dimensional multi-modal functions while preserving the dynamic correlation between the components. The test applies to a wide class of (non-stationary) covariance structures of the response, and it detects a significant group difference based on a single p-value, thereby overcoming the issue of adjusting for multiple p-values that arise due to comparing the means in each of components separately. Finite-sample numerical studies demonstrate that the test maintains the type-I error, and is powerful to detect significant group differences, compared to the state-of-the-art testing procedures. The test is carried out on two significant longitudinal studies for Alzheimer's disease and Parkinson's disease (PD) patients, namely, TOMMORROW study of individuals at high risk of mild cognitive impairment to detect differences in the cognitive test scores between the pioglitazone and the placebo groups, and Azillect study to assess the efficacy of rasagiline as a potential treatment to slow down the progression of PD.

RevDate: 2024-02-27

Zakaria N, Wan Harun WMRS, Mohammad Latif MA, et al (2024)

Effects of anthocyanidins on the conformational transition of Aβ(1-42) peptide: Insights from molecular docking and molecular dynamics simulations.

Journal of molecular graphics & modelling, 129:108732 pii:S1093-3263(24)00032-9 [Epub ahead of print].

Recent evidence from in vitro and in vivo studies has shown that anthocyanins and anthocyanidins can reduce and inhibit the amyloid beta (Aβ) species, one of the hallmarks of Alzheimer's disease (AD). However, their inhibition mechanisms on Aβ species at molecular details remain elusive. Therefore, in the present study, molecular modelling methods were employed to investigate their inhibitory mechanisms on Aβ(1-42) peptide. The results highlighted that anthocyanidins effectively inhibited the conformational transitions of helices into beta-sheet (β-sheet) conformation within Aβ(1-42) peptide by two different mechanisms: 1) the obstruction of two terminals from coming into contact due to the binding of anthocyanidins with residues of N- and second hydrophobic core (SHC)-C-terminals, and 2) the prevention of the folding process due to the binding of anthocyanidin with the central polar (Asp23 and Lys28) and native helix (Asp23, Lys28, and Leu34) residues. These new findings on the inhibition of β-sheet formation by targeting both N- and SHC-C-terminals, and the long-established target, D23-K28 salt bridge residues, not with the conventional central hydrophobic core (CHC) as reported in the literature, might aid in designing more potent inhibitors for AD treatment.

RevDate: 2024-02-27

Xiao Y, Zhang Y, Li L, et al (2024)

Cynaroside extends lifespan and improves the neurondegeneration diseases via insulin/IGF-1 signaling pathway in Caenorhabditis elegans.

Archives of gerontology and geriatrics, 122:105377 pii:S0167-4943(24)00053-0 [Epub ahead of print].

The evolutionarily conserved insulin/IGF-1 signaling pathway plays a central role in aging and aging related diseases such as neurodegeneration diseases. Inhibition of insulin/IGF-1 signaling pathway has been proposed as an effective way to extend lifespan and delay neurodegeneration diseases in different organisms. Cynaroside (Cyn), a flavonoid contained in many medical plants and in vegetables, had been shown to exhibit pharmacological properties such as anti-inflammatory, anti-tumor, and anti-oxidant effects. The study demonstrated that lifespan extension and neurodegeneration diseases improving could be achieved by targeting evolutionarily conserved insulin/IGF-1 pathway through using pharmacological interventions. Via using this approach in tractable model Caenorhabditis elegans, we found that 10 μM Cynaroside significantly promoted the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Cynaroside acted on IGF-1-R /DAF-2, which was followed by the activation of transcription factor DAF-16/FOXO to extend the healthy lifespan. Intriguingly, Cynaroside also improved neurodegeneration diseases such as Alzheimer's and polyglutamine disease by suppressing insulin/IGF-1 signaling pathway. Our work suggests that Cynaroside may be a promising candidate for the prevention and treatment of aging and neurodegeneration diseases.

RevDate: 2024-02-27

Brokate-Llanos AM, Sanchez-Ibañez M, Pérez-Jiménez MM, et al (2024)

Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's Disease.

G3 (Bethesda, Md.) pii:7615242 [Epub ahead of print].

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous Genome Wide Association Study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (Gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homologue, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of Gemcitabine, showed animprovement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentration. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in microglia N13 cell line. Thus, inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly Gemcitabine might be considered as a promising candidate to be repurposed for its treatment.

RevDate: 2024-02-27

Gurung K, Šimek P, Jegorov A, et al (2024)

Structure and absolute configuration of natural fungal product beauveriolide I, isolated from Cordyceps javanica, determined by 3D electron diffraction.

Acta crystallographica. Section C, Structural chemistry pii:S2053229624001359 [Epub ahead of print].

Beauveriolides, including the main beauveriolide I {systematic name: (3R,6S,9S,13S)-9-benzyl-13-[(2S)-hexan-2-yl]-6-methyl-3-(2-methylpropyl)-1-oxa-4,7,10-triazacyclotridecane-2,5,8,11-tetrone, C27H41N3O5}, are a series of cyclodepsipeptides that have shown promising results in the treatment of Alzheimer's disease and in the prevention of foam cell formation in atherosclerosis. Their crystal structure studies have been difficult due to their tiny crystal size and fibre-like morphology, until now. Recent developments in 3D electron diffraction methodology have made it possible to accurately study the crystal structures of submicron crystals by overcoming the problems of beam sensitivity and dynamical scattering. In this study, the absolute structure of beauveriolide I was determined by 3D electron diffraction. The cyclodepsipeptide crystallizes in the space group I2 with lattice parameters a = 40.2744 (4), b = 5.0976 (5), c = 27.698 (4) Å and β = 105.729 (6)°. After dynamical refinement, its absolute structure was determined by comparing the R factors and calculating the z-scores of the two possible enantiomorphs of beauveriolide I.

RevDate: 2024-02-28
CmpDate: 2024-02-28

Scott IA (2024)

Monoclonal antibodies for treating early Alzheimer disease-a commentary on recent 'positive' trials.

Age and ageing, 53(2):.

Recent phase 3 randomised controlled trials of amyloid-targeting monoclonal antibodies in people with pre-clinical or early Alzheimer disease have reported positive results, raising hope of finally having disease-modifying drugs. Given their far-reaching implications for clinical practice, the methods and findings of these trials, and the disease causation theory underpinning the mechanism of drug action, need to be critically appraised. Key considerations are the representativeness of trial populations; balance of prognostic factors at baseline; psychometric properties and minimal clinically important differences of the primary efficacy outcome measures; level of study fidelity; consistency of subgroup analyses; replication of findings in similar trials; sponsor role and potential conflicts of interest; consistency of results with disease causation theory; cost and resource estimates; and alternative prevention and treatment strategies. In this commentary, we show shortcomings in each of these areas and conclude that monoclonal antibody treatment for early Alzheimer disease is lacking high-quality evidence of clinically meaningful impacts at an affordable cost.

RevDate: 2024-02-27

Urmila A, Kundlik R, D Mathure (2024)

Effectiveness of Novel Drug Delivery System using Curcumin in Alzheimer's Disease.

Central nervous system agents in medicinal chemistry pii:CNSAMC-EPUB-138734 [Epub ahead of print].

Alzheimer's disease (AD) is a form of brain degeneration that gradually impairs a person's memory and cognitive skills, eventually making it harder for them to perform everyday activities. Its pathophysiology has been attributed to the deposition of amyloid β (Aβ), neurofibrillary tangles (NFT), and α-synuclein (A-s) in some cases. Presently, 4 drugs have been approved for the treatment. They are Donepezil, Rivastigmine, Galantamine and Memantine. The first three are acetylcholinesterase inhibitors, while memantine is an NMDA receptor antagonist. Even though these medications are successful in treating mild to moderate Alzheimer's disease, they have not been able to reverse the disease or even slow its progression completely. Hence, natural products are gaining more popularity due to the advantage of the multitarget intervention effect. The most investigated spice, Curcuma longa's bioactive component, curcumin, has demonstrated anti-amyloid, anti-NFT, and anti-Lewy body properties and substantial antiinflammatory, antioxidant, and antiapoptotic properties. However, its proven neuroprotective activity is hampered by many factors, such as poor water solubility and bioavailability. Therefore, many novel formulations have been designed to improve its bioavailability with methods such as 1) Micellar Solubilization, 2) Cyclodextrin Complexation, 3) Crystal Modification, and 4) Particle Size Reduction, etc. The current chapter aims to summarize various novel formulations of curcumin and their effectiveness in treating AD.

RevDate: 2024-02-28
CmpDate: 2024-02-28

Luz IS, Takaya R, Ribeiro DG, et al (2024)

Proteomics: Unraveling the Cross Talk Between Innate Immunity and Disease Pathophysiology, Diagnostics, and Treatment Options.

Advances in experimental medicine and biology, 1443:221-242.

Inflammation is crucial in diseases, and proteins play a key role in the interplay between innate immunity and pathology. This review explores how proteomics helps understanding this relationship, focusing on diagnosis and treatment. We explore the dynamic innate response and the significance of proteomic techniques in deciphering the complex network of proteins involved in prevalent diseases, including infections, cancer, autoimmune and neurodegenerative disorders. Proteomics identifies key proteins in host-pathogen interactions, shedding light on infection mechanisms and inflammation. These discoveries hold promise for diagnostic tools, therapies, and vaccines. In cancer research, proteomics reveals innate signatures associated with tumor development, immune evasion, and therapeutic response. Additionally, proteomic analysis has unveiled autoantigens and dysregulation of the innate immune system in autoimmunity, offering opportunities for early diagnosis, disease monitoring, and new therapeutic targets. Moreover, proteomic analysis has identified altered protein expression patterns in neurodegenerative diseases like Alzheimer's and Parkinson's, providing insights into potential therapeutic strategies. Proteomics of the innate immune system provides a comprehensive understanding of disease mechanisms, identifies biomarkers, and enables effective interventions in various diseases. Despite still in its early stages, this approach holds great promise to revolutionize innate immunity research and significantly improve patient outcomes across a wide range of diseases.

RevDate: 2024-02-27

Yan C, Grabowska ME, Dickson AL, et al (2024)

Leveraging generative AI to prioritize drug repurposing candidates for Alzheimer's disease with real-world clinical validation.

NPJ digital medicine, 7(1):46.

Drug repurposing represents an attractive alternative to the costly and time-consuming process of new drug development, particularly for serious, widespread conditions with limited effective treatments, such as Alzheimer's disease (AD). Emerging generative artificial intelligence (GAI) technologies like ChatGPT offer the promise of expediting the review and summary of scientific knowledge. To examine the feasibility of using GAI for identifying drug repurposing candidates, we iteratively tasked ChatGPT with proposing the twenty most promising drugs for repurposing in AD, and tested the top ten for risk of incident AD in exposed and unexposed individuals over age 65 in two large clinical datasets: (1) Vanderbilt University Medical Center and (2) the All of Us Research Program. Among the candidates suggested by ChatGPT, metformin, simvastatin, and losartan were associated with lower AD risk in meta-analysis. These findings suggest GAI technologies can assimilate scientific insights from an extensive Internet-based search space, helping to prioritize drug repurposing candidates and facilitate the treatment of diseases.

RevDate: 2024-02-27

Shang NY, Huang LJ, Lan JQ, et al (2024)

PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Acta pharmacologica Sinica [Epub ahead of print].

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg[-1]·d[-1], i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

RevDate: 2024-02-26

Zhang Z, Ding C, Fu R, et al (2024)

Low-frequency rTMS modulated the excitability and high-frequency firing in hippocampal neurons of the Alzheimer's disease mouse model.

Brain research pii:S0006-8993(24)00076-3 [Epub ahead of print].

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, holds potential for applications in the treatment of Alzheimer's disease (AD). This study aims to compare the therapeutic effects of rTMS at different frequencies on Alzheimer's disease and explore the alterations in neuronal electrophysiological properties throughout this process. APP/PS1 AD mice were subjected to two rTMS treatments at 0.5 Hz and 20 Hz, followed by assessments of therapeutic outcomes through the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tests. Following this, whole-cell patch-clamp techniques were used to record action potential, voltage-gated sodium channel currents, and voltage-gated potassium channel currents in dentate gyrus granule neurons. The results show that AD mice exhibit significant cognitive decline compared to normal mice, along with a pronounced reduction in neuronal excitability and ion channel activity. Both frequencies of rTMS treatment partially reversed these changes, demonstrating similar therapeutic efficacy. Furthermore, the investigation indicates that low-frequency magnetic stimulation inhibited the concentrated firing of early action potentials in AD.

RevDate: 2024-02-26

González-Cota AL, Martínez-Flores D, Rosendo-Pineda MJ, et al (2024)

NMDA receptor-mediated Ca[2+] signaling: Impact on cell cycle regulation and the development of neurodegenerative diseases and cancer.

Cell calcium, 119:102856 pii:S0143-4160(24)00014-9 [Epub ahead of print].

NMDA receptors are Ca[2+]-permeable ligand-gated ion channels that mediate fast excitatory transmission in the central nervous system. NMDA receptors regulate the proliferation and differentiation of neural progenitor cells and also play critical roles in neural plasticity, memory, and learning. In addition to their physiological role, NMDA receptors are also involved in glutamate-mediated excitotoxicity, which results from excessive glutamate stimulation, leading to Ca[2+] overload, and ultimately to neuronal death. Thus, NMDA receptor-mediated excitotoxicity has been linked to several neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, dementia, and stroke. Interestingly, in addition to its effects on cell death, aberrant expression or activation of NMDA receptors is also involved in pathological cellular proliferation, and is implicated in the invasion and proliferation of various types of cancer. These disorders are thought to be related to the contribution of NMDA receptors to cell proliferation and cell death through cell cycle modulation. This review aims to discuss the evidence implicating NMDA receptor activity in cell cycle regulation and the link between aberrant NMDA receptor activity and the development of neurodegenerative diseases and cancer due to cell cycle dysregulation. The information presented here will provide insights into the signaling pathways and the contribution of NMDA receptors to these diseases, and suggests that NMDA receptors are promising targets for the prevention and treatment of these diseases, which are leading causes of death and disability worldwide.

RevDate: 2024-02-26

Wang B, Pan X, Teng IT, et al (2024)

Functional Selection of Tau Oligomerization-Inhibiting Aptamers.

Angewandte Chemie (International ed. in English) [Epub ahead of print].

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd = 6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

RevDate: 2024-02-26

Munafó JP, Biscussi B, Obiol D, et al (2024)

New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System.

ACS chemical neuroscience [Epub ahead of print].

Cholinergic deficit is a characteristic factor of several pathologies, such as myasthenia gravis, some types of congenital myasthenic syndromes, and Alzheimer's Disease. Two molecular targets for its treatment are acetylcholinesterase (AChE) and nicotinic acetylcholine receptor (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Here, we present new bifunctional caffeine derivatives consisting of a theophylline ring connected to amino groups by different linkers. All of them were more potent AChE inhibitors than caffeine. Furthermore, although some of them also activated muscle nAChR as partial agonists, not all of them stabilized nAChR in its desensitized conformation. To understand the molecular mechanism underlying these results, we performed docking studies on AChE and nAChR. The nAChR agonist behavior of the compounds depends on their accessory group, whereas their ability to stabilize the receptor in a desensitized state depends on the interactions of the linker at the binding site. Our results show that the new compounds can inhibit AChE and activate nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in cholinergic deficit.

RevDate: 2024-02-26

Wen Q, Wittens MMJ, Engelborghs S, et al (2024)

Beyond CSF and Neuroimaging Assessment: Evaluating Plasma miR-145-5p as a Potential Biomarker for Mild Cognitive Impairment and Alzheimer's Disease.

ACS chemical neuroscience [Epub ahead of print].

Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening. Cerebrospinal fluid (CSF) biomarkers such as amyloid β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau181 (P-tau181) levels are core biomarkers for early diagnosis of AD. Several studies have proposed the use of blood-circulating microRNAs (miRNAs) as potential novel early biomarkers for AD. We therefore applied a novel approach to identify blood-circulating miRNAs associated with CSF biomarkers and explored the potential of these miRNAs as biomarkers of AD. In total, 112 subjects consisting of 28 dementia due to AD cases, 63 MCI due to AD cases, and 21 cognitively healthy controls were included. We identified seven Aβ1-42-associated plasma miRNAs, six P-tau181-associated plasma miRNAs, and nine Aβ1-42-associated serum miRNAs. These miRNAs were involved in AD-relevant biological processes, such as PI3K/AKT signaling. Based on this signaling pathway, we constructed an miRNA-gene target network, wherein miR-145-5p has been identified as a hub. Furthermore, we showed that miR-145-5p performs best in the prediction of both AD and MCI. Moreover, miR-145-5p also improved the prediction performance of the mini-mental state examination (MMSE) score. The performance of this miRNA was validated using different datasets including an RT-qPCR dataset from plasma samples of 23 MCI cases and 30 age-matched controls. These findings indicate that blood-circulating miRNAs that are associated with CSF biomarkers levels and specifically plasma miR-145-5p alone or combined with the MMSE score can potentially be used as noninvasive biomarkers for AD or MCI screening in the general population, although studies in other AD cohorts are necessary for further validation.

RevDate: 2024-02-27

Xie Y, Li S, Wu D, et al (2024)

Vitamin K: Infection, Inflammation, and Auto-Immunity.

Journal of inflammation research, 17:1147-1160.

Vitamin K (VK) comprises a group of substances with chlorophyll quinone bioactivity and exists in nature in the form of VK1 and VK2. As its initial recognition originated from the ability to promote blood coagulation, it is known as the coagulation vitamin. However, based on extensive research, VK has shown potential for the prevention and treatment of various diseases. Studies demonstrating the beneficial effects of VK on immunity, antioxidant capacity, intestinal microbiota regulation, epithelial development, and bone protection have drawn growing interest in recent years. This review article focuses on the mechanism of action of VK and its potential preventive and therapeutic effects on infections (eg, asthma, COVID-19), inflammation (eg, in type 2 diabetes mellitus, Alzheimer's disease, Parkinson's disease, cancer, aging, atherosclerosis) and autoimmune disorders (eg, inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis). In addition, VK-dependent proteins (VKDPs) are another crucial mechanism by which VK exerts anti-inflammatory and immunomodulatory effects. This review explores the potential role of VK in preventing aging, combating neurological abnormalities, and treating diseases such as cancer and diabetes. Although current research appoints VK as a therapeutic tool for practical clinical applications in infections, inflammation, and autoimmune diseases, future research is necessary to elucidate the mechanism of action in more detail and overcome current limitations.

RevDate: 2024-02-27

Jiang X, Li J, Yao X, et al (2024)

Neuroprotective effects of dipeptidyl peptidase 4 inhibitor on Alzheimer's disease: a narrative review.

Frontiers in pharmacology, 15:1361651.

Insulin resistance in brain and amyloidogenesis are principal pathological features of diabetes-related cognitive decline and development of Alzheimer's disease (AD). A growing body of evidence suggests that maintaining glucose under control in diabetic patients is beneficial for preventing AD development. Dipeptidyl peptidase 4 inhibitors (DDP4is) are a class of novel glucose-lowering medications through increasing insulin excretion and decreasing glucagon levels that have shown neuroprotective potential in recent studies. This review consolidates extant evidence from earlier and new studies investigating the association between DPP4i use, AD, and other cognitive outcomes. Beyond DPP4i's benefits in alleviating insulin resistance and glucose-lowering, underlying mechanisms for the potential neuroprotection with DPP4i medications were categorized into the following sections: (Ferrari et al., Physiol Rev, 2021, 101, 1,047-1,081): the benefits of DPP4is on directly ameliorating the burden of β-amyloid plaques and reducing the formation of neurofibrillary tangles; DPP4i increasing the bioactivity of neuroprotective DPP4 substrates including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and stromal-derived factor-1α (SDF-1α) etc.; pleiotropic effects of DPP4is on neuronal cells and intracerebral structure including anti-inflammation, anti-oxidation, and anti-apoptosis. We further revisited recently published epidemiological studies that provided supportive data to compliment preclinical evidence. Given that there remains a lack of completed randomized trials that aim at assessing the effect of DPP4is in preventing AD development and progression, this review is expected to provide a useful insight into DPP4 inhibition as a potential therapeutic target for AD prevention and treatment. The evidence is helpful for informing the rationales of future clinical research and guiding evidence-based clinical practice.

RevDate: 2024-02-27

Pinjala P, Tryphena KP, Kulkarni A, et al (2024)

Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP[+] Iodide-Induced Parkinson's Disease Mice Model.

Journal of Alzheimer's disease reports, 8(1):329-344.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration.

OBJECTIVE: To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models.

METHODS: The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP[+] exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP[+] iodide+DMF 15 mg/kg), Mid Dose (MPP[+] iodide+DMF 30 mg/kg), and High Dose (MPP[+] iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR.

RESULTS: DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP[+] iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group.

CONCLUSIONS: DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.

RevDate: 2024-02-27

Sleem T, Decourt B, MN Sabbagh (2024)

Nonmedication Devices in Development for the Treatment of Alzheimer's Disease.

Journal of Alzheimer's disease reports, 8(1):241-255.

Huge investments continue to be made in treatment for Alzheimer's disease (AD), with more than one hundred drugs currently in development. Pharmacological approaches and drug development, particularly those targeting amyloid-β, have dominated the therapeutic landscape. At the same time, there is also a growing interest in devices for treating AD. This review aimed to identify and describe devices under development for AD treatment. In this review, we queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2021 using the terms "device," "therapeutics," and "Alzheimer's" for articles that report on devices to treat AD. Ten devices with 31 references were identified as actively being developed for the treatment of AD. Many of these devices are far along in development. Device-based therapies are often overlooked when evaluating treatment approaches to AD. However, many devices for treating AD are in development and some show promising results.

RevDate: 2024-02-27

Garcia MJ, Leadley R, Ross J, et al (2024)

Prognostic and Predictive Factors in Early Alzheimer's Disease: A Systematic Review.

Journal of Alzheimer's disease reports, 8(1):203-240.

BACKGROUND: Alzheimer's disease (AD) causes progressive decline of cognition and function. There is a lack of systematic literature reviews on prognostic and predictive factors in its early clinical stages (eAD), i.e., mild cognitive impairment due to AD and mild AD dementia.

OBJECTIVE: To identify prognostic factors affecting eAD progression and predictive factors for treatment efficacy and safety of approved and/or under late-stage development disease-modifying treatments.

METHODS: Databases were searched (August 2022) for studies reporting prognostic factors associated with eAD progression and predictive factors for treatment response. The Quality in Prognostic Factor Studies tool or the Cochrane risk of bias tool were used to assess risk of bias. Two reviewers independently screened the records. A single reviewer performed data extraction and quality assessment. A second performed a 20% check. Content experts reviewed and interpreted the data collected.

RESULTS: Sixty-one studies were included. Self-reporting, diagnosis definition, and missing data led to high risk of bias. Population size ranged from 110 to 11,451. Analyses found data indicating that older age was and depression may be associated with progression. Greater baseline cognitive impairment was associated with progression. APOE4 may be a prognostic factor, a predictive factor for treatment efficacy and predicts an adverse response (ARIA). Elevated biomarkers (CSF/plasma p-tau, CSF t-tau, and plasma neurofilament light) were associated with disease progression.

CONCLUSIONS: Age was the strongest risk factor for progression. Biomarkers were associated with progression, supporting their use in trial selection and aiding diagnosis. Baseline cognitive impairment was a prognostic factor. APOE4 predicted ARIA, aligning with emerging evidence and relevant to treatment initiation/monitoring.

RevDate: 2024-02-27

Pohl F, Lindsay-McGee V, Kong Thoo Lin P, et al (2024)

Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model.

microPublication biology, 2024:.

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of C. elegans and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity.

RevDate: 2024-02-27
CmpDate: 2024-02-27

Kuang BY, Zhu YC, Liang JP, et al (2024)

[Exosome and prevention of Alzheimer's disease: based on theory of kidney storing essence].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 49(1):55-61.

The theory of kidney storing essence storage, an important part of the basic theory of traditional Chinese medicine(TCM), comes from the Chapter 9 Discussion on Six-Plus-Six System and the Manifestations of the Viscera in the Plain Questions, which says that "the kidney manages closure and is the root of storage and the house of Jing(Essence)". According to this theory, essence is the fundamental substance of human life activities and it is closely related to the growth and development of the human body. Alzheimer's disease(AD) is one of the common neurodegenerative diseases, with the main pathological features of Aβ deposition and Tau phosphorylation, which activate neurotoxic reactions and eventually lead to neuronal dysfunction and cell death, severely impairing the patient's cognitive and memory functions. Although research results have been achieved in the TCM treatment of AD, the complex pathogenesis of AD makes it difficult to develop the drugs capable of curing AD. The stem cell therapy is an important method to promote self-repair and regeneration, and bone marrow mesenchymal stem cells(BMSCs) as adult stem cells have the ability of multi-directional differentiation. By reviewing the relevant literature, this paper discusses the association between BMSCs and the TCM theory of kidney storing essence, and expounds the material basis of this theory from the perspective of molecular biology. Studies have shown that TCM with the effect of tonifying the kidney in the treatment of AD are associated with BMSCs. Exosomes produced by such cells are one of the main substances affecting AD. Exosomes containing nucleic acids, proteins, and lipids can participate in intercellular communication, regulate cell function, and affect AD by reducing Aβ deposition, inhibiting Tau protein phosphorylation and neuroinflammation, and promoting neuronal regeneration. Therefore, discussing the prevention and treatment of exosomes and AD based on the theory of kidney storing essence will provide a new research idea for the TCM treatment of AD.

RevDate: 2024-02-25

Park JI, Alzheimer's Disease Neuroimaging Initiative (2024)

Prevalence of mild behavioural impairment and its association with cognitive and functional impairment in normal cognition, mild cognitive impairment, and mild Alzheimer's dementia.

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society [Epub ahead of print].

BACKGROUND: Mild behavioural impairment (MBI) is an emergent and persistent neuropsychiatric symptom (NPS) in subjects aged 50 and older who are at risk for cognitive decline. We examined the prevalence of MBI across the spectrum from cognitively normal (CN), mild cognitive impairment (MCI), to dementia, and further investigated the association between the MBI domain and cognitive and functional impairment.

METHOD: MBI was assessed in 2337 elderly patients in the Alzheimer's Disease Neuroimaging Initiative database (mean age, 73.04 years; 52.8% male). Among the subjects, 868 (37.1%) had normal cognition, 1066 (45.6%) had MCI, and 403 (17.2%) had mild Alzheimer's dementia (AD). MBI was evaluated in accordance with the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment diagnostic criteria for MBI, utilising the Neuropsychiatric Inventory. We compared the prevalence of the MBI domain with CN using multinominal logistic regression analysis and further quantified the magnitude of the association between MCI/AD and the MBI domains by calculating the population attributable risk (PAR). We assessed the association between the MBI domains and cognitive and functional impairment using simultaneous linear regression analysis.

RESULTS: The most common MBI domains in each diagnostic group were affective dysregulation followed by impulse dyscontrol, decreased motivation, social inappropriateness, and abnormal perception or thought content. The PARs for MBI domains in subjects with MCI or AD were respectively: 16.60% and 24.34% for affective dysregulation; 3.72% and 18.06% for impulse dyscontrol; 4.78% and 14.13% for decreased motivation, 1.91% and 2.29% for social inappropriateness; and 0.68% and 3.85% for abnormal perception or thought content. All MBI domains except for social inappropriateness were significantly associated with a higher 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale total score. All MBI domains were significantly associated with a higher Functional Activities Questionnaire total score.

CONCLUSION: Our findings show that MBI is highly prevalent across subjects with CN, MCI, and AD and is associated with cognitive and functional decline. MBI could be a crucial clinical phenotype relevant to the risk of cognitive and functional impairment, and provides a useful dimension pertinent to diagnostic approaches.

RevDate: 2024-02-24

Lei T, Yang Z, Li H, et al (2024)

Interactions between nanoparticles and pathological changes of vascular in Alzheimer's disease.

Advanced drug delivery reviews pii:S0169-409X(24)00041-3 [Epub ahead of print].

Emerging evidence suggests that vascular pathological changes play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The dysfunction of the cerebral vasculature occurs in the early course of AD, characterized by alterations in vascular morphology, diminished cerebral blood flow (CBF), impairment of the neurovascular unit (NVU), vasculature inflammation, and cerebral amyloid angiopathy. Vascular dysfunction not only facilitates the influx of neurotoxic substances into the brain, triggering inflammation and immune responses but also hampers the efflux of toxic proteins such as Aβ from the brain, thereby contributing to neurodegenerative changes in AD. Furthermore, these vascular changes significantly impact drug delivery and distribution within the brain. Therefore, developing targeted delivery systems or therapeutic strategies based on vascular alterations may potentially represent a novel breakthrough in AD treatment. This review comprehensively examines various aspects of vascular alterations in AD and outlines the current interactions between nanoparticles and pathological changes of vascular.

RevDate: 2024-02-24

Pei MQ, Xu LM, Yang YS, et al (2024)

Latest advances and clinical application prospects of resveratrol therapy for neurocognitive disorders.

Brain research pii:S0006-8993(24)00075-1 [Epub ahead of print].

Neurocognitive disorders, such as Alzheimer's disease, vascular dementia, and postoperative cognitive dysfunction, are non-psychiatric brain syndromes in which a significant decline in cognitive function causes great trauma to the mental status of the patient. The lack of effective treatments for neurocognitive disorders imposes a considerable burden on society, including a substantial economic impact. Over the past few decades, the identification of resveratrol, a natural plant compound, has provided researchers with an opportunity to formulate novel strategies for the treatment of neurocognitive disorders. This is because resveratrol effectively protects the brain of those with neurocognitive disorders by targeting some mechanisms such as inflammation and oxidative stress. This article reviews the status of recent research investigating the use of resveratrol for the treatment of different neurocognitive disorders. By examining the possible mechanisms of action of resveratrol and the shared mechanisms of different neurocognitive disorders, treatments for neurocognitive disorders may be further clarified.

RevDate: 2024-02-24

Wang G, Li Y, Xiong C, et al (2024)

Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab.

METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker.

RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes.

DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials.

HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.

RevDate: 2024-02-24

Bouabdallah S, Brinza I, Boiangiu RS, et al (2024)

The Effect of a Tribulus-Based Formulation in Alleviating Cholinergic System Impairment and Scopolamine-Induced Memory Loss in Zebrafish (Danio rerio): Insights from Molecular Docking and In Vitro/In Vivo Approaches.

Pharmaceuticals (Basel, Switzerland), 17(2):.

Tribulus terrestris L. (Tt) has been recently gaining attention for its pharmacological value, including its neuroprotective activities. In this study, we explore the neuroprotective effects of a Tribulus terrestris extract in a zebrafish (Danio rerio) model of scopolamine (SCOP)-induced memory impairment and brain oxidative stress. SCOP, an anticholinergic drug, was employed to replicate fundamental aspects of Alzheimer's disease (AD) in animal models. The fish were treated with ethanolic leaf extract (ELE) from Tt (1, 3, and 6 mg/L) for 15 days. SCOP (100 µM) was administered 30 min before behavioral tests were conducted. Molecular interactions of the major compounds identified via UPLC-PDA/MS in Tt fractions with the active site of acetylcholinesterase (AChE) were explored via molecular docking analyses. Terrestrosin C, protodioscin, rutin, and saponin C exhibited the most stable binding. The spatial memory performance was assessed using the Y-maze test, and memory recognition was examined using a novel object recognition (NOR) test. Tt extract treatment reversed the altered locomotion patterns that were caused by SCOP administration. Biochemical analyses also verified Tt's role in inhibiting AChE, improving antioxidant enzyme activities, and reducing oxidative stress markers. The present findings pave the way for future application of Tt as a natural alternative to treat cognitive disorders.

RevDate: 2024-02-24

Cha Y, Kagalwala MN, J Ross (2024)

Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.

Pharmaceuticals (Basel, Switzerland), 17(2):.

Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.

RevDate: 2024-02-24

Tashima T (2024)

Mesenchymal Stem Cell (MSC)-Based Drug Delivery into the Brain across the Blood-Brain Barrier.

Pharmaceutics, 16(2):.

At present, stem cell-based therapies using induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) are being used to explore the potential for regenerative medicine in the treatment of various diseases, owing to their ability for multilineage differentiation. Interestingly, MSCs are employed not only in regenerative medicine, but also as carriers for drug delivery, homing to target sites in injured or damaged tissues including the brain by crossing the blood-brain barrier (BBB). In drug research and development, membrane impermeability is a serious problem. The development of central nervous system drugs for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, remains difficult due to impermeability in capillary endothelial cells at the BBB, in addition to their complicated pathogenesis and pathology. Thus, intravenously or intraarterially administered MSC-mediated drug delivery in a non-invasive way is a solution to this transendothelial problem at the BBB. Substances delivered by MSCs are divided into artificially included materials in advance, such as low molecular weight compounds including doxorubicin, and expected protein expression products of genetic modification, such as interleukins. After internalizing into the brain through the fenestration between the capillary endothelial cells, MSCs release their cargos to the injured brain cells. In this review, I introduce the potential and advantages of drug delivery into the brain across the BBB using MSCs as a carrier that moves into the brain as if they acted of their own will.

RevDate: 2024-02-26
CmpDate: 2024-02-26

Abdelhamid M, Jung CG, Zhou C, et al (2024)

Potential Therapeutic Effects of Bifidobacterium breve MCC1274 on Alzheimer's Disease Pathologies in App[NL-G-F] Mice.

Nutrients, 16(4):.

We previously demonstrated that orally supplemented Bifidobacterium breve MCC1274 (B. breve MCC1274) mitigated Alzheimer's disease (AD) pathologies in both 7-month-old App[NL-G-F] mice and wild-type mice; thus, B. breve MCC1274 supplementation might potentially prevent the progression of AD. However, the possibility of using this probiotic as a treatment for AD remains unclear. Thus, we investigated the potential therapeutic effects of this probiotic on AD using 17-month-old App[NL-G-F] mice with memory deficits and amyloid beta saturation in the brain. B. breve MCC1274 supplementation ameliorated memory impairment via an amyloid-cascade-independent pathway. It reduced hippocampal and cortical levels of phosphorylated extracellular signal-regulated kinase and c-Jun N-terminal kinase as well as heat shock protein 90, which might have suppressed tau hyperphosphorylation and chronic stress. Moreover, B. breve MCC1274 supplementation increased hippocampal synaptic protein levels and upregulated neuronal activity. Thus, B. breve MCC1274 supplementation may alleviate cognitive dysfunction by reducing chronic stress and tau hyperphosphorylation, thereby enhancing both synaptic density and neuronal activity in 17-month-old App[NL-G-F] mice. Overall, this study suggests that B. breve MCC1274 has anti-AD effects and can be used as a potential treatment for AD.

RevDate: 2024-02-24

Reiss AB, Gulkarov S, Jacob B, et al (2024)

Mitochondria in Alzheimer's Disease Pathogenesis.

Life (Basel, Switzerland), 14(2):.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

RevDate: 2024-02-24

Nohesara S, Abdolmaleky HM, S Thiagalingam (2024)

Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases.

Biomedicines, 12(2):.

Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains of patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer's disease (AD) and autism may be attributed to mitochondrial dysfunction and changes in energy metabolism. While neuronal activity is associated with reduction in brain pH, astrocytes are responsible for rebalancing the pH to maintain the equilibrium. As lactate level is the main determinant of brain pH, neuronal activities are impacted by pH changes due to the binding of protons (H[+]) to various types of proteins, altering their structure and function in the neuronal and non-neuronal cells of the brain. Lactate and pH could affect diverse types of epigenetic modifications, including histone lactylation, which is linked to histone acetylation and DNA methylation. In this review, we discuss the importance of pH homeostasis in normal brain function, the role of lactate as an essential epigenetic regulatory molecule and its contributions to brain pH abnormalities in neuropsychiatric diseases, and shed light on lactate-based and pH-modulating therapies in neuropsychiatric diseases by targeting epigenetic modifications. In conclusion, we attempt to highlight the potentials and challenges of translating lactate-pH-modulating therapies to clinics for the treatment of neuropsychiatric diseases.

RevDate: 2024-02-24

Faraji P, Borchert A, Ahmadian S, et al (2024)

Butylated Hydroxytoluene (BHT) Protects SH-SY5Y Neuroblastoma Cells from Ferroptotic Cell Death: Insights from In Vitro and In Vivo Studies.

Antioxidants (Basel, Switzerland), 13(2):.

Ferroptosis is a special kind of programmed cell death that has been implicated in the pathogenesis of a large number of human diseases. It involves dysregulated intracellular iron metabolism and uncontrolled lipid peroxidation, which together initiate intracellular ferroptotic signalling pathways leading to cellular suicide. Pharmacological interference with ferroptotic signal transduction may prevent cell death, and thus patients suffering from ferroptosis-related diseases may benefit from such treatment. Butylated hydroxytoluene (BHT) is an effective anti-oxidant that is frequently used in oil chemistry and in cosmetics to prevent free-radical-mediated lipid peroxidation. Since it functions as a radical scavenger, it has previously been reported to interfere with ferroptotic signalling. Here, we show that BHT prevents RSL3- and ML162-induced ferroptotic cell death in cultured human neuroblastoma cells (SH-SY5Y) in a dose-dependent manner. It prevents the RSL3-induced oxidation of membrane lipids and normalises the RSL3-induced inhibition of the intracellular catalytic activity of glutathione peroxidase 4. The systemic application of BHT in a rat Alzheimer's disease model prevented the upregulation of the expression of ferroptosis-related genes. Taken together, these data indicate that BHT interferes with ferroptotic signalling in cultured neuroblastoma cells and may prevent ferroptotic cell death in an animal Alzheimer's disease model.

RevDate: 2024-02-24

Jo SL, EJ Hong (2024)

Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

Antioxidants (Basel, Switzerland), 13(2):.

Alzheimer's disease (AD) is the leading cause of dementia and is one of the neurodegenerative diseases that are caused by neuronal death due to various triggers. Neuroinflammation plays a critical role in the development of AD. The neuroinflammatory response is manifested by pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; various chemokines; nitrous oxide; and reactive oxygen species. In this study, we evaluated the relevance of progesterone receptor membrane component 1 (PGRMC1), which is expressed in the brain cells during the induction of neuroinflammation. A lipopolysaccharide (LPS)-induced chronic neuroinflammation model and Pgrmc1 knockdown cells were used to assess the inflammatory cytokine levels, AD-related factors, inflammation-related signaling, and cell death. Pgrmc1 knockout (KO) mice had higher IL-1β levels after treatment with LPS compared with those of wild-type (WT) mice. Furthermore, Pgrmc1 KO mice had higher levels of inflammatory factors, endoplasmic reticulum stress indicators, and AD-associated markers compared with those of WT mice who underwent LPS treatment or not. Finally, these indicators were observed in vitro using U373-MG astrocytes. In conclusion, the loss of PGRMC1 may promote neuroinflammation and lead to AD.

RevDate: 2024-02-24

Fišar Z, J Hroudová (2024)

CoQ10 and Mitochondrial Dysfunction in Alzheimer's Disease.

Antioxidants (Basel, Switzerland), 13(2):.

The progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aβ) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

RevDate: 2024-02-24

Kim S, Yoon H, SK Park (2024)

Butein Increases Resistance to Oxidative Stress and Lifespan with Positive Effects on the Risk of Age-Related Diseases in Caenorhabditis elegans.

Antioxidants (Basel, Switzerland), 13(2):.

Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer's disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson's disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.

RevDate: 2024-02-24

Thongsopha C, Chaiwut T, Thaweekhotr P, et al (2024)

Aegle marmelos (L.) Leaf Extract Improves Symptoms of Memory Loss Induced by Scopolamine in Rats.

Foods (Basel, Switzerland), 13(4):.

Alzheimer's disease (AD) is the most common neurodegenerative disease that results in memory impairment. Aegle marmelos (L.) Correa (AM) is used as a traditional medicine. AM leaves have the potential to inhibit acetylcholinesterase activity. This study used scopolamine to induce AD in rats. The aim of this study was to investigate the effects of AM leaf extract using this model. Motor and memory functions were tested by the motor activity and Morris water maze (MWM) tests, respectively. The density of the synaptophysin and dendritic spines in the CA1 were detected by immunofluorescence and Golgi impregnation, respectively. The hippocampal histology was reviewed by H&E staining. After the treatment, the latency times in the MWM tests of the AD groups reduced, while the motor activities showed no difference. The density of the synaptophysin of the AD groups increased after the treatments, and that of the dendritic spines also increased in all AD groups post-treatment. The hippocampal tissue also recovered. AM leaf extract can improve cognitive impairment in AD models by maintaining the presynaptic vesicle proteins and dendritic spines in a dose-dependent manner.

RevDate: 2024-02-26
CmpDate: 2024-02-26

Li R, Li Y, Zuo H, et al (2024)

Alzheimer's Amyloid-β Accelerates Cell Senescence and Suppresses SIRT1 in Human Neural Stem Cells.

Biomolecules, 14(2):.

As a lifelong source of neurons, neural stem cells (NSCs) serve multiple crucial functions in the brain. The senescence of NSCs may be associated with the onset and progression of Alzheimer's disease (AD). Our study reveals a noteworthy finding, indicating that the AD-associated pathogenic protein amyloid-β (Aβ) substantially enhances senescence-related characteristics of human NSCs. These characteristics encompass the enhanced expression of p16 and p21, the upregulation of genes associated with the senescence-associated secretory phenotype (SASP), increased SA-β-gal activity, and the activation of the DNA damage response. Further studies revealed that Aβ treatment significantly downregulates the SIRT1 protein which plays a crucial role in regulating the aging process and decreases downstream PGC-1α and FOXO3. Subsequently, we found that SIRT1 overexpression significantly alleviates a range of Aβ-induced senescent markers in human NSCs. Taken together, our results uncover that Aβ accelerates cellular senescence in human NSCs, making SIRT1 a highly promising therapeutic target for senescent NSCs which may contribute to age-related neurodegenerative diseases, including AD.

RevDate: 2024-02-24

Liu J, MM Mouradian (2024)

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases.

International journal of molecular sciences, 25(4):.

Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer's disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson's disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington's disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

RevDate: 2024-02-24

Bae SJ, Lee WY, Bak SB, et al (2024)

Antioxidant Efficacy of Hwangryunhaedok-tang through Nrf2 and AMPK Signaling Pathway against Neurological Disorders In Vivo and In Vitro.

International journal of molecular sciences, 25(4):.

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aβ), and Aβ-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09[®]), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aβ, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.

RevDate: 2024-02-24

Hasantari I, Nicolas N, Alzieu P, et al (2024)

Factor H's Control of Complement Activation Emerges as a Significant and Promising Therapeutic Target for Alzheimer's Disease Treatment.

International journal of molecular sciences, 25(4): pii:ijms25042272.

The complement is a component of the innate immune system designed to fight infections and tissue- or age-related damages. Complement activation creates an inflammatory microenvironment, which enhances cell death. Excessive complement inflammatory activity has been linked to alterations in the structure and functions of the blood-brain barrier, contributing to a poor prognosis for Alzheimer's disease (AD). In the AD preclinical phase, individuals are often clinically asymptomatic despite evidence of AD neuropathology coupled with heightened inflammation. Considering the involvement of the complement system in the risk of developing AD, we hypothesize that inhibiting complement activation could reduce this inflammatory period observed even before clinical signs, thereby slowing down the onset/progression of AD. To validate our hypothesis, we injected complement inhibitor factor H into the brain of APP/PS1 AD mice at early or late stages of this pathology. Our results showed that the injection of factor H had effects on both the onset and progression of AD by reducing proinflammatory IL6, TNF-α, IL1β, MAC and amyloid beta levels. This reduction was associated with an increase in VGLUT1 and Psd95 synaptic transmission in the hippocampal region, leading to an improvement in cognitive functions. This study invites a reconsideration of factor H's therapeutic potential for AD treatment.

RevDate: 2024-02-24

Mast N, Li Y, IA Pikuleva (2024)

7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.

International journal of molecular sciences, 25(4): pii:ijms25042242.

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer's disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer's disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid β40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.

RevDate: 2024-02-24

Cho SB (2024)

Comorbidity Genes of Alzheimer's Disease and Type 2 Diabetes Associated with Memory and Cognitive Function.

International journal of molecular sciences, 25(4): pii:ijms25042211.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are comorbidities that result from the sharing of common genes. The molecular background of comorbidities can provide clues for the development of treatment and management strategies. Here, the common genes involved in the development of the two diseases and in memory and cognitive function are reviewed. Network clustering based on protein-protein interaction network identified tightly connected gene clusters that have an impact on memory and cognition among the comorbidity genes of AD and T2DM. Genes with functional implications were intensively reviewed and relevant evidence summarized. Gene information will be useful in the discovery of biomarkers and the identification of tentative therapeutic targets for AD and T2DM.

RevDate: 2024-02-24

Sheikh AM, Yano S, Tabassum S, et al (2024)

The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications.

International journal of molecular sciences, 25(4): pii:ijms25042169.

Degenerative diseases, encompassing a wide range of conditions affecting various organ systems, pose significant challenges to global healthcare systems. This comprehensive review explores the intricate interplay between the vascular system and degenerative diseases, shedding light on the underlying mechanisms and profound implications for disease progression and management. The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denominator of degenerative diseases across multiple systems. In the nervous system, we explored the influence of vascular factors on neurodegenerative diseases such as Alzheimer's and Parkinson's, emphasizing the critical role of cerebral blood flow regulation and the blood-brain barrier. Within the kidney system, the intricate relationship between vascular health and chronic kidney disease is scrutinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding vascular involvement in degenerative diseases and potential therapeutic interventions targeting vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a profound appreciation of the role of the vascular system in degenerative diseases is essential for advancing our understanding of degenerative disease pathogenesis and developing innovative approaches for prevention and treatment. This review provides a comprehensive foundation for researchers, clinicians, and policymakers seeking to address the intricate relationship between vascular health and degenerative diseases in pursuit of improved patient outcomes and enhanced public health.

RevDate: 2024-02-23

Liu X, Chen J, Du Y, et al (2024)

The changes of neurogenesis in the hippocampal dentate gyrus of SAMP8 mice and the effects of acupuncture and moxibustion.

Brain research pii:S0006-8993(24)00068-4 [Epub ahead of print].

BACKGROUND: Influenced by the global aging population, the incidence of Alzheimer's disease (AD) has increased sharply. In addition to increasing β-amyloid plaque deposition and tau tangle formation, neurogenesis dysfunction has recently been observed in AD. Therefore, promoting regeneration to improve neurogenesis and cognitive dysfunction can play an effective role in AD treatment. Acupuncture and moxibustion have been widely used in the clinical treatment of neurodegenerative diseases because of their outstanding advantages such as early, functional, and benign two-way adjustment. It is urgent to clarify the effectiveness, greenness, and safety of acupuncture and moxibustion in promoting neurogenesis in AD treatment.

METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice at various ages were used as experimental models to simulate the pathology and behaviors of AD mice. Behavioral experiments, immunohistochemistry, Western blot, and immunofluorescence experiments were used for comparison between different groups.

RESULTS: Acupuncture and moxibustion could increase the number of PCNA[+] DCX[+] cells, Nissl bodies, and mature neurons in the hippocampal Dentate gyrus (DG) of SAMP8 mice, restore the hippocampal neurogenesis, delay the AD-related pathological presentation, and improve the learning and memory abilities of SAMP8 mice.

CONCLUSION: The pathological process underlying AD and cognitive impairment were changed positively by improving the dysfunction of neurogenesis. This indicates the promising role of acupuncture and moxibustion in the prevention and treatment of AD.

RevDate: 2024-02-23

Pumo A, S Legeay (2024)

The dichotomous activities of microglia: A potential driver for phenotypic heterogeneity in Alzheimer's disease.

Brain research pii:S0006-8993(24)00071-4 [Epub ahead of print].

Alzheimer's disease (AD) is a leading cause of dementia, characterized by two defining neuropathological hallmarks: amyloid plaques composed of Aβ aggregates and neurofibrillary pathology. Recent research suggests that microglia have both beneficial and detrimental effects in the development of AD. A new theory proposes that microglia play a beneficial role in the early stages of the disease but become harmful in later stages. Further investigations are needed to gain a comprehensive understanding of this shift in microglia's function. This transition is likely influenced by specific conditions, including spatial, temporal, and transcriptional factors, which ultimately lead to the deterioration of microglial functionality. Additionally, recent studies have also highlighted the potential influence of microglia diversity on the various manifestations of AD. By deciphering the multiple states of microglia and the phenotypic heterogeneity in AD, significant progress can be made towards personalized medicine and better treatment outcomes for individuals affected by AD.

RevDate: 2024-02-23

Liu Y, Tan Y, Cheng G, et al (2024)

Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction Against Alzheimer's Disease.

Advanced materials (Deerfield Beach, Fla.) [Epub ahead of print].

The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species (ROS) overproduction. However, the treatment of AD remains challenging owning to the hinderance caused by the blood-brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) was used as a drug carrier as well as an antioxidant and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP-MB. For intranasal delivery, we fabricated a thermosensitive hydrogel by cross-linking carboxymethyl chitosan (CMCS) and aldehyde Pluronic F127 (F127-CHO) micelles. The BP-MB nanocomposite was incorporated into the hydrogel to obtain BP-MB@Gel. BP-MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After intranasal administration, BP-MB was continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating the neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain-targeted drug delivery in the management of the complex pathologies of AD. This article is protected by copyright. All rights reserved.

RevDate: 2024-02-23

Vera R, Hong N, Jiang B, et al (2024)

Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice.

Journal of Alzheimer's disease : JAD pii:JAD231337 [Epub ahead of print].

BACKGROUND: Repurposing dantrolene to treat Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy.

OBJECTIVE: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated.

METHODS: The bioavailability of intranasal ERFR was measured in 2 and 9-11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test).

RESULTS: The dantrolene concentration in the blood and brain decreased with age, with the decrease greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein.

CONCLUSIONS: Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice.

RevDate: 2024-02-23

Greenblatt CL, R Lathe (2024)

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia.

Journal of Alzheimer's disease : JAD pii:JAD231323 [Epub ahead of print].

There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.

RevDate: 2024-02-23

Anand ST, Vo AD, La J, et al (2024)

Severe COVID-19 in Vaccinated Adults With Hematologic Cancers in the Veterans Health Administration.

JAMA network open, 7(2):e240288 pii:2815441.

IMPORTANCE: With SARS-CoV-2 transforming into an endemic disease and with antiviral treatments available, it is important to establish which patients remain at risk of severe COVID-19 despite vaccination.

OBJECTIVE: To quantify the associations of clinical and demographic variables with odds of severe COVID-19 among patients with hematologic cancers.

This case-control study included all patients with hematologic malignant neoplasms in the national Veterans Health Administration (VHA) who had documented SARS-CoV-2 infection after vaccination. Groups of patients with severe (cases) vs nonsevere (controls) COVID-19 were compared. Data were collected between January 1, 2020, and April 5, 2023, with data on infection collected between January 1, 2021, and September 30, 2022. All patients with diagnostic codes for hematologic malignant neoplasms who had documented vaccination followed by documented SARS-CoV-2 infection and for whom disease severity could be assessed were included. Data were analyzed from July 28 to December 30, 2023.

EXPOSURES: Clinical (comorbidities, predominant viral variant, treatment for malignant neoplasm, booster vaccination, and antiviral treatment) and demographic (age and sex) variables shown in prior studies to be associated with higher or lower rates of severe COVID-19. Comorbidities included Alzheimer disease or dementia, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, heart failure, and peripheral vascular disease.

MAIN OUTCOME AND MEASURES: The main outcome was severe COVID-19 compared with nonsevere SARS-CoV-2 infection. Severe COVID-19 was defined as death within 28 days, mechanical ventilation, or hospitalization with use of dexamethasone or evidence of hypoxemia or use of supplemental oxygen. Multivariable logistic regression was used to estimate the associations of demographic and clinical variables with the odds of severe COVID-19, expressed as adjusted odds ratios (aORs) with 95% CIs.

RESULTS: Among 6122 patients (5844 [95.5%] male, mean [SD] age, 70.89 [11.57] years), 1301 (21.3%) had severe COVID-19. Age (aOR per 1-year increase, 1.05; 95% CI, 1.04-1.06), treatment with antineoplastic or immune-suppressive drugs (eg, in combination with glucocorticoids: aOR, 2.32; 95% CI, 1.93-2.80), and comorbidities (aOR per comorbidity, 1.35; 95% CI, 1.29-1.43) were associated with higher odds of severe disease, whereas booster vaccination was associated with lower odds (aOR, 0.73; 95% CI, 0.62-0.86). After oral antiviral drugs became widely used in March 2022, 20 of 538 patients (3.7%) with SARS-CoV-2 infection during this period had progression to severe COVID-19.

CONCLUSIONS AND RELEVANCE: In this case-control study of patients with hematologic cancers, odds of severe COVID-19 remained high through mid-2022 despite vaccination, especially in patients requiring treatment.

RevDate: 2024-02-24

Alhattab M, Moorthy LS, Patel D, et al (2024)

Oleaginous Microbial Lipids' Potential in the Prevention and Treatment of Neurological Disorders.

Marine drugs, 22(2):.

The products of oleaginous microbes, primarily lipids, have gained tremendous attention for their health benefits in food-based applications as supplements. However, this emerging biotechnology also offers a neuroprotective treatment/management potential for various diseases that are seldom discussed. Essential fatty acids, such as DHA, are known to make up the majority of brain phospholipid membranes and are integral to cognitive function, which forms an important defense against Alzheimer's disease. Omega-3 polyunsaturated fatty acids have also been shown to reduce recurrent epilepsy seizures and have been used in brain cancer therapies. The ratio of omega-3 to omega-6 PUFAs is essential in maintaining physiological function. Furthermore, lipids have also been employed as an effective vehicle to deliver drugs for the treatment of diseases. Lipid nanoparticle technology, used in pharmaceuticals and cosmeceuticals, has recently emerged as a biocompatible, biodegradable, low-toxicity, and high-stability means for drug delivery to address the drawbacks associated with traditional medicine delivery methods. This review aims to highlight the dual benefit that lipids offer in maintaining good health for disease prevention and in the treatment of neurological diseases.

RevDate: 2024-02-24

Kim KH, Lim SH, Hwang JH, et al (2024)

Inhibition of Glial Activation and Subsequent Reduction in White Matter Damage through Supplementation with a Combined Extract of Wheat Bran, Citrus Peel, and Jujube in a Rat Model of Vascular Dementia.

Current issues in molecular biology, 46(2):1485-1502.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. In our previous studies, we showed that wheat bran extract (WBE) reduced white matter damage in a rat VaD model and improved memory in a human clinical trial. However, starch gelatinization made the large-scale preparation of WBE difficult. To simplify the manufacturing process and increase efficacy, we attempted to find a decoction containing an optimum ratio of wheat bran, sliced citrus peel, and sliced jujube (WCJ). To find an optimal ratio, the cell survival of C6 (rat glioma) cultured under hypoxic conditions (1% O2) was measured, and apoptosis was assessed. To confirm the efficacies of the optimized WCJ for VaD, pupillary light reflex, white matter damage, and the activation of astrocytes and microglia were assessed in a rat model of bilateral common carotid artery occlusion (BCCAO) causing chronic hypoperfusion. Using a combination of both searching the literature and cell survival experiments, we chose 6:2:1 as the optimal ratio of wheat bran to sliced citrus peel to sliced jujube to prepare WCJ. We showed that phytic acid contained only in wheat bran can be used as an indicator component for the quality control of WCJ. We observed in vitro that the WCJ treatment improved cell survival by reducing apoptosis through an increase in the Bcl-2/Bax ratio. In the BCCAO experiments, the WCJ-supplemented diet prevented astrocytic and microglial activation, mitigated myelin damage in the corpus callosum and optic tract, and, consequently, improved pupillary light reflex at dosages over 100 mg/kg/day. The results suggest that the consumption of WCJ can prevent VaD by reducing white matter damage, and WCJ can be developed as a safe, herbal medicine to prevent VaD.

RevDate: 2024-02-24

Savall ASP, de Mello JD, Fidelis EM, et al (2024)

Nanoencapsulated Curcumin: Enhanced Efficacy in Reversing Memory Loss in An Alzheimer Disease Model.

Brain sciences, 14(2):.

Investigating new drugs or formulations that target Alzheimer disease (AD) is critical for advancing therapeutic interventions. Therefore, this study aimed to assess the effectiveness of nanoencapsulated curcumin (NC Curc) in alleviating memory impairment, oxidative stress, and neuroinflammation in a validated AD model. Male Wistar rats were given bilateral intracerebroventricular injections of either saline or streptozotocin (STZ) (3 mg/3 µL/site) to establish the AD model (day 0). On day 22, daily oral administrations of curcumin (6 mg/kg), NC Curc (6 mg/kg), or a vehicle (unloaded NC) were initiated and continued for 14 days. NC Curc significantly reversed memory deficits in object recognition and inhibitory avoidance tests induced by STZ. Both formulations of curcumin attenuated elevated acetylcholinesterase activity caused by STZ. Importantly, NC Curc alone effectively mitigated STZ-induced oxidative stress. Additionally, NC Curc treatment normalized GFAP levels, suggesting a potential reduction in neuroinflammation in STZ-treated rats. Our findings indicate that NC Curc improves memory in an AD rat model, highlighting its enhanced therapeutic effects compared to unencapsulated curcumin. This research significantly contributes to understanding the therapeutic and neurorestorative potential of NC Curc in AD, particularly in reversing pathophysiological changes.

RevDate: 2024-02-23

Paillard T, Blain H, PL Bernard (2024)

The impact of exercise on Alzheimer's disease progression.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: The preventive effects of chronic physical exercise (CPE) on Alzheimer's disease (AD) are now admitted by the scientific community. Curative effects of CPE are more disputed, but they deserve to be investigated, since CPE is a natural non-pharmacological alternative for the treatment of AD.

AREAS COVERED: In this perspective, the authors discuss the impact of CPE on AD based on an exhaustive literature search using the electronic databases PubMed, ScienceDirect and Google Scholar.

EXPERT OPINION: Aerobic exercise alone is probably not the unique solution and needs to be complemented by other exercises (physical activities) to optimize the slowing down of AD. Anaerobic, muscle strength and power, balance/coordination and meditative exercises may also help to slow down the AD progression. However, the scientific evidence does not allow a precise description of the best training program for patients with AD. Influential environmental conditions (e.g. social relations, outdoor or indoor exercise) should also be studied to optimize training programs aimed at slowing down the AD progression.

RevDate: 2024-02-24

Hong JM, Munna AN, Moon JH, et al (2024)

Melatonin-mediated calcineurin inactivation attenuates amyloid beta-induced apoptosis.

IBRO neuroscience reports, 16:336-344.

Alzheimer's disease (AD) is the most common age-related progressive neurodegenerative disorder. The accumulation of amyloid beta-peptide is a neuropathological marker of AD. While melatonin is recognized to have protective effects on aging and neurodegenerative disorders, the therapeutic effect of melatonin on calcineurin in AD is poorly understood. In this study, we examined the effect and underlying molecular mechanisms of melatonin treatment on amyloid beta-mediated neurotoxicity in neuroblastoma cells. Melatonin treatment decreased calcineurin and autophagy in neuroblastoma cells. Electron microscopy images showed that melatonin inhibited amyloid beta-induced autophagic vacuoles. The increase in the amyloid beta-induced apoptosis rate was observed more in PrPC-expressing ZW cells than in PrPC-silencing Zpl cells. Taken together, the results suggest that by mitigating the effect of calcineurin and autophagy flux activation, melatonin could also rescue amyloid beta-induced neurotoxic effects. These findings may be relevant to therapy for neurodegenerative diseases, including AD.

RevDate: 2024-02-24

Bu J, Mahan Y, Zhang S, et al (2024)

Acacetin inhibits inflammation by blocking MAPK/NF-κB pathways and NLRP3 inflammasome activation.

Frontiers in pharmacology, 15:1286546.

Objective: Our preliminary research indicates that acacetin modulates the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome, providing protection against Alzheimer's Disease (AD) and cerebral ischemic reperfusion injury. The mechanisms of acacetin to inhibit the activation of the NLRP3 inflammasome remain fully elucidated. This study aims to investigate the effects and potential mechanisms of acacetin on various agonists induced NLRP3 inflammasome activation. Methods: A model for the NLRP3 inflammasome activation was established in mouse bone marrow-derived macrophages (BMDMs) using Monosodium Urate (MSU), Nigericin, Adenosine Triphosphate (ATP), and Pam3CSK4, separately. Western blot analysis (WB) was employed to detect Pro-caspase-1, Pro-Interleukin-1β (Pro-IL-1β) in cell lysates, and caspase-1, IL-1β in supernatants. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measured the release of IL-1β, IL-18, and Tumor Necrosis Factor-alpha (TNF-α) in cell supernatants to assess the impact of acacetin on NLRP3 inflammasome activation. The lactate dehydrogenase (LDH) release was also assessed. The Nuclear Factor Kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways related proteins were evaluated by WB, and NF-κB nuclear translocation was observed via laser scanning confocal microscopy (LSCM). Disuccinimidyl Suberate (DSS) cross-linking was employed to detect oligomerization of Apoptosis-associated Speck-like protein containing a Caspase Recruitment Domain (ASC), and LSCM was also used to observe Reactive Oxygen Species (ROS) production. Inductively Coupled Plasma (ICP) and N-(6-methoxyquinolyl) acetoethyl ester (MQAE) assays were utilized to determined the effects of acacetin on the efflux of potassium (K+) and chloride (Cl-) ions. Results: Acacetin inhibited NLRP3 inflammasome activation induced by various agonists, reducing the release of TNF-α, IL-1β, IL-18, and LDH. It suppressed the expression of Lipopolysaccharides (LPS)-activated Phosphorylated ERK (p-ERK), p-JNK, and p-p38, inhibited NF-κB p65 phosphorylation and nuclear translocation. Acacetin also reduced ROS production and inhibited ASC aggregation, thus suppressing NLRP3 inflammasome activation. Notably, acacetin did not affect K+ and Cl-ions efflux during the activation process. Conclusion: Acacetin shows inhibitory effects on both the priming and assembly processes of the NLRP3 inflammasome, positioning it as a promising new candidate for the treatment of NLRP3 inflammasome-related diseases.

RevDate: 2024-02-24

Teipel SJ, Temp AGM, MW Lutz (2024)

Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease.

Alzheimer's & dementia (New York, N. Y.), 10(1):e12454.

INTRODUCTION: Phase 3 trials using the anti-amyloid antibodies aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease dementia were heterogeneous in respect to statistical significance of effects. However, heterogeneity of results has not yet directly be quantified.

METHODS: We used Bayesian random effects meta-analysis to quantify evidence for or against a treatment effect, and assessed the size of the effect and its heterogeneity. Data were extracted from published studies where available and Web based data reports, assuming a Gaussian data generation process.

RESULTS: We found moderate evidence in favor of a treatment effect (Bayes factor = 13.2). The effect was moderate to small with -0.33 (95% credible interval -0.54 to -0.10) points on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale. The heterogeneity parameter was low to moderate with 0.21 (0.04 to 0.45) CDR-SB points.

DISCUSSION: Heterogeneity across studies was moderate despite some trials reaching statistical significance, while others did not. This suggests that the negative aducanumab and gantenerumab trials are in full agreement with the expected effect sizes.

RevDate: 2024-02-22

Mao Y, Yuan W, Gai J, et al (2024)

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

International journal of pharmaceutics pii:S0378-5173(24)00164-9 [Epub ahead of print].

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-β-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-β-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

RevDate: 2024-02-22

Fleisher AS, Munsie LM, Perahia DGS, et al (2024)

Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.

Neurology, 102(5):e208061.

BACKGROUND AND OBJECTIVES: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD).

METHODS: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology.

RESULTS: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs.

DISCUSSION: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification.

ClinicalTrials.gov: NCT03518073.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

RevDate: 2024-02-24

Fatmi MK, Wang H, Slotabec L, et al (2024)

Single-Cell RNA-seq reveals transcriptomic modulation of Alzheimer's disease by activated protein C.

Aging, 16: pii:205624 [Epub ahead of print].

Single-Cell RNA sequencing reveals changes in cell population in Alzheimer's disease (AD) model 5xFAD (5x Familial AD mutation) versus wild type (WT) mice. The returned sequencing data was processed through the 10x Genomics CellRanger platform to perform alignment and form corresponding matrix to perform bioinformatic analysis. Alterations in glial cells occurred in 5xFAD versus WT, especially increases in microglia proliferation were profound in 5xFAD. Differential expression testing of glial cells in 5xFAD versus WT revealed gene regulation. Globally, the critical genes implicated in AD progression are upregulated such as Apoe, Ctsb, Trem2, and Tyrobp. Using this differential expression data, GO term enrichment was completed to observe possible biological processes impacted by AD progression. Utilizing anti-inflammatory and cyto-protective recombinant Activated Protein C (APC), we uncover inflammatory processes to be downregulated by APC treatment in addition to recuperation of nervous system processes. Moreover, animal studies demonstrated that administration of recombinant APC significantly attenuated Aβ burden and improved cognitive function of 5xFAD mice. The downregulation of highly expressed AD biomarkers in 5xFAD could provide insight into the mechanisms by which APC administration benefits AD.

RevDate: 2024-02-22

Ademowo OS, Oyebode O, Edward R, et al (2024)

Effects of carotenoids on mitochondrial dysfunction.

Biochemical Society transactions pii:234092 [Epub ahead of print].

Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.

RevDate: 2024-02-24

Zhang S, Guo Z, Xu Y, et al (2024)

Transcranial magneto-acoustic stimulation improves spatial memory and modulates hippocampal neural oscillations in a mouse model of Alzheimer's disease.

Frontiers in neuroscience, 18:1313639.

INTRODUCTION: In our study, we applied transcranial magneto-acoustic stimulation (TMAS), a technique based on focused ultrasound stimulation within a static magnetic field, in the APP/PS1 mouse model of Alzheimer's disease (AD) to explore the feasibility of TMAS on improving AD related spatial memory deficits and abnormal neural oscillations.

METHODS: The mice treated with TMAS once daily for 21 days. We recorded local field potential signals in the hippocampal CA1 region of the mice after TMAS treatment with in-vivo electrophysiology and evaluated the neural rehabilitative effect of TMAS with sharp-wave ripple (SWR), gamma oscillations during SWRs, and phase-amplitude coupling (PAC). The spatial memory function of the mice was examined by the Morris water maze (MWM) task.

RESULTS: We found that TMAS improved the performance of MWM related spatial cognitive functions compared with AD group. Furthermore, our results implied that TMAS alleviated abnormalities in hippocampal SWRs, increased slow gamma power during SWRs, and promoted theta-slow gamma phase-amplitude coupling. These findings suggest that TMAS could have a positive influence on spatial memory through the modulation of neural oscillations.

DISCUSSION: This work emphasizes the potential of TMAS to serve as a non-invasive method for Alzheimer's disease rehabilitation and promote the application of TMAS for the treatment of more neurological and brain aging diseases in the future.

RevDate: 2024-02-21

Wong E, Malviya M, Jain T, et al (2024)

HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling.

Molecular psychiatry [Epub ahead of print].

CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of β-amyloid 42 (Aβ42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD.

RevDate: 2024-02-24
CmpDate: 2024-02-23

Shoaip N, El-Sappagh S, Abuhmed T, et al (2024)

A dynamic fuzzy rule-based inference system using fuzzy inference with semantic reasoning.

Scientific reports, 14(1):4275.

The challenge of making flexible, standard, and early medical diagnoses is significant. However, some limitations are not fully overcome. First, the diagnosis rules established by medical experts or learned from a trained dataset prove static and too general. It leads to decisions that lack adaptive flexibility when finding new circumstances. Secondly, medical terminological interoperability is highly critical. It increases realism and medical progress and avoids isolated systems and the difficulty of data exchange, analysis, and interpretation. Third, criteria for diagnosis are often heterogeneous and changeable. It includes symptoms, patient history, demographic, treatment, genetics, biochemistry, and imaging. Symptoms represent a high-impact indicator for early detection. It is important that we deal with these symptoms differently, which have a great relationship with semantics, vary widely, and have linguistic information. This negatively affects early diagnosis decision-making. Depending on the circumstances, the diagnosis is made solo on imaging and some medical tests. In this case, although the accuracy of the diagnosis is very high, can these decisions be considered an early diagnosis or prove the condition is deteriorating? Our contribution in this paper is to present a real medical diagnostic system based on semantics, fuzzy, and dynamic decision rules. We attempt to integrate ontology semantics reasoning and fuzzy inference. It promotes fuzzy reasoning and handles knowledge representation problems. In complications and symptoms, ontological semantic reasoning improves the process of evaluating rules in terms of interpretability, dynamism, and intelligence. A real-world case study, ADNI, is presented involving the field of Alzheimer's disease (AD). The proposed system has indicated the possibility of the system to diagnose AD with an accuracy of 97.2%, 95.4%, 94.8%, 93.1%, and 96.3% for AD, LMCI, EMCI, SMC, and CN respectively.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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