Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK

Cell Metabolism, Год журнала: 2024, Номер 36(6), С. 1351 - 1370.e8

Опубликована: Апрель 23, 2024

Язык: Английский

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Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 27, 2025

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to involvement of lipid dysregulation in development AD. Nevertheless, precise lipidomic landscape and mechanistic roles lipids pathology remain poorly understood. This review aims highlight significance lipidomics lipid-targeting approaches diagnosis We summarized connection between human brain AD at both genetic species levels. briefly introduced technologies discussed potential challenges areas future advancements field for research. To elucidate central role converging multiple pathological aspects AD, we reviewed current knowledge on interplay major features, including amyloid beta, tau, neuroinflammation. Finally, assessed progresses obstacles lipid-based therapeutics proposed strategies leveraging

Язык: Английский

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Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors

Nature Neuroscience, Год журнала: 2023, Номер 26(12), С. 2131 - 2146

Опубликована: Ноя. 9, 2023

Social behaviors are innate and supported by dedicated neural circuits, but the molecular identities of these circuits how they established developmentally shaped experience remain unclear. Here we show that medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages have distinct response patterns functions in social behavior male mice. MeA expressing transcription factor Foxp2 (MeA

Язык: Английский

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Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 6901 - 6901

Опубликована: Июнь 24, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD associated with cognitive decline memory loss that worsens aging. A statistical report using U.S. data on estimates approximately 6.9 million suffer from AD, a number projected to surge 13.8 by 2060. Thus, there critical imperative pinpoint address its hallmark tau protein aggregation early prevent manage debilitating effects. Amyloid-β proteins are primarily formation plaques neurofibril tangles in brain. Current research efforts focus degrading amyloid-β or inhibiting their synthesis, particularly targeting APP processing hyperphosphorylation, aiming develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies trials treatments truly make difference. Genome-wide association (GWASs) across various cohorts identified 40 loci over 300 genes AD. Despite wealth genetic data, much remains be understood about functions these role process, prompting continued investigation. By delving deeper into associations, novel targets such as kinases, proteases, cytokines, degradation pathways, offer new directions for drug discovery therapeutic intervention This review delves biological pathways disrupted identifies how variations within could serve potential treatment strategies. Through comprehensive understanding molecular underpinnings researchers aim pave way more therapies can alleviate burden devastating disease.

Язык: Английский

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Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes

Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), molecular mechanisms underlying isoform-dependent risk and relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 decreases uptake cholesteryl esters (CEs), which are linked to neurodegeneration. In human neurons, addition ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 ApoE2) associated lipofuscinosis, age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased accumulation tau fibrils was elevated in APOE4 mouse brain exacerbation by pathology. Intrahippocampal injection PUFA-CE-lipApoE4 sufficient induce lipofuscinosis wild-type mice. Finally, protective Christchurch mutation also reduced phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD reducing deleterious effects endolysosomal targeting pathogenic lipids.

Язык: Английский

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Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(9), С. 6590 - 6605

Опубликована: Июль 19, 2024

Abstract INTRODUCTION The apolipoprotein E gene ( APOE ) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. influences not only amyloid‐beta and tau pathologies but also lipid energy metabolism, neuroinflammation, cerebral vascular health, sex‐dependent manifestations. Furthermore, ancestral background may significantly impact link between AD, underscoring need for more inclusive research. METHODS In 2023, Association convened multidisciplinary researchers at “AAIC Advancements: APOE” conference to discuss various topics, including their roles AD pathogenesis, progress apoE‐targeted therapeutic strategies, updates on models interventions that modulate expression function. RESULTS This manuscript presents highlights from provides overview opportunities further research field. DISCUSSION Understanding apoE's multifaceted will help develop targeted advance field precision medicine. Highlights a disease. exerts numerous effects throughout brain amyloid‐beta, tau, other pathways. AAIC encouraged discussions collaborations understanding role APOE.

Язык: Английский

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From Lab Bench to Hope: Emerging Gene Therapies in Clinical Trials for Alzheimer’s Disease

Molecular Neurobiology, Год журнала: 2024, Номер unknown

Опубликована: Июль 3, 2024

Язык: Английский

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Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy

Science Translational Medicine, Год журнала: 2025, Номер 17(781)

Опубликована: Янв. 15, 2025

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of brain immune system, especially orchestrated by microglia, plays an important role onset and progression. Thus, a major question how modulate phenotype function microglia treat Xenon (Xe) gas noble used human patients as anesthetic neuroprotectant for treating injuries. Xe penetrates blood-brain barrier, which could make it effective therapeutic. To assess effect on AD pathology, we designed custom inhalation chamber treated several mouse models with gas. treatment induced adopt intermediate activation state have termed pre–neurodegenerative (pre-MGnD). This microglial phenotypic transition was observed acute neurodegeneration amyloidosis (APP/PS1 5xFAD mice) tauopathy (P301S mice). enhanced amyloid plaque compaction reduced dystrophic neurites APP/PS1 models. Moreover, atrophy neuroinflammation improved nest-building behavior P301S mice. Mechanistically, toward pre-MGnD through IFN-γ signaling maintained phagocytic response mice while suppressing proinflammatory These results support translation approach

Язык: Английский

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Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer’s disease-associated pathology in a 3xTg-AD mouse model

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 184, С. 117895 - 117895

Опубликована: Фев. 6, 2025

Язык: Английский

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