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

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 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.

Language: Английский

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Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Language: Английский

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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 926 - 946

Published: Aug. 6, 2024

Language: Английский

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Lysosomes in senescence and aging

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(11)

Published: Oct. 9, 2023

Language: Английский

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Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: June 8, 2023

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have linked to lysosomal de-acidification through impairing vacuolar-type ATPase ion channels on organelle membrane. Similar abnormalities are also present sporadic forms neurodegeneration, although underlying pathogenic mechanisms unclear remain be investigated. Importantly, recent studies revealed early occurrence impairment before onset neurodegeneration late-stage pathology. However, there is lack methods for pH monitoring vivo dearth lysosome-acidifying therapeutic agents. Here, we summarize evidence notion defective an indicator urge critical need technological advancement developing tools detection both clinical applications. We further discuss current preclinical pharmacological agents that modulate acidification, small molecules nanomedicine, their potential translation into lysosome-targeting therapies. Both timely development therapeutics restore function represent paradigm shifts targeting diseases.

Language: Английский

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Presenilins as hub proteins controlling the endocytic and autophagic pathways and small extracellular vesicle secretion

Journal of Extracellular Vesicles, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 1, 2025

Abstract Emerging evidence indicates that autophagy is tightly connected to the endocytic pathway. Here, we questioned role of presenilins (PSENs 1 and 2), previously shown be involved in regulation, secretion small endocytic‐originating extracellular vesicles known as exosomes. Indeed, while wild‐type cells responded stimuli promoting both multivesicular endosome (MVE) formation (sEVs) enriched canonical exosomal proteins, PSEN‐deficient were almost unaffected these stimuli. Moreover, cells, re‐expression either PSEN1 or functional active PSEN1delta9 mutant led a rescue most sEV secretion, deletion alone fully phenocopied total PSEN invalidation. We found lack was also due overactivated MVEs degradation rather than plasma membrane fusion. Hence, autophagic blocker bafilomycin A1 (BafA1) not only increased intracellular levels MVE protein CD63, but turned on by stimulating autophagy‐dependent unconventional secretion. In case, sEVs arised from amphisomes proteins lysosomal‐autophagy‐associated cargo. Altogether, here demonstrate PSENs, particularly PSEN1, act hub controlling balance between endosomal/autophagic More generally, our findings strengthen view strong interconnection pathways their complementary roles

Language: Английский

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Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 18, 2025

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar early-onset (EOAD) late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 4.07 (82.1 6.37 controls (66.4 13.04). identified differentially abundant proteins when comparing plaques neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in 132), 192), 128), 43 plaque-associated shared across all groups. Positive correlations were observed between (R2 .77), .73), .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p 1.29 × 10−5) for immune system regulation 4.33 lysosome organization 0.029) LOAD. Protein networks revealed a protein signature involving metabolism, response, functions. In vs. control tissue, we 263, 269, 301 proteins, 65 altered cohorts. Non-plaque showed modest .59) .33) compared correlation .79). GOBP term groups was chromatin remodeling 0.001), additional terms including extracellular matrix, protein–DNA complexes expression Our study reveals key functional characteristics amyloid LOAD, highlighting pathways endo/lysosomal functions responses. The distinct alterations ECM structure, underscoring unique differences subtypes. findings enhance our understanding pathogenesis identify potential biomarkers therapeutic targets.

Language: Английский

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Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(4), P. 625 - 634

Published: Jan. 5, 2024

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of leading causes disability worldwide. The apolipoprotein E4 gene (APOE4) strongest genetic risk factor for AD. In 2023, APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data discuss question whether reduce or increase as a therapeutic intervention It was unanimous consensus that cumulative from multiple studies in humans animal models support lowering should be target approaches carriers. ANN NEUROL 2024;95:625-634.

Language: Английский

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New precision medicine avenues to the prevention of Alzheimer’s disease from insights into the structure and function of γ-secretases

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(6), P. 887 - 903

Published: Feb. 23, 2024

Abstract Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer’s disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in context earlier small molecules described “γ-secretase modulators” (GSM). We review here structure, function, and pathobiology γ-secretases, a focus on how mutations presenilin genes result early-onset AD. Significant progress has been made generating compounds that act manner opposite to pathogenic mutations: they stabilize proteinase-substrate complex, thereby increasing processivity substrate cleavage altering size spectrum Aβ peptides produced. propose term allosteric stabilizers” (GSAS) distinguish these from rather heterogenous class GSM. The GSAS represent, theory, precision medicine approach prevention amyloid deposition, specifically target discrete aspect complex cell biological signalling mechanism initiates pathological processes leading disease.

Language: Английский

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Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(12), P. 1571 - 1592.e9

Published: April 15, 2024

Neuronal endosomal and lysosomal abnormalities are among the early changes observed in Alzheimer's disease (AD) before plaques appear. However, it is unclear whether distinct endolysosomal defects temporally organized how altered γ-secretase function or amyloid precursor protein (APP) metabolism contribute to these changes. Inhibiting chronically, mouse embryonic fibroblast hippocampal neurons, led a gradual collapse initiated by decreased calcium increased cholesterol, causing downstream recycling maturation. This demise dependent, requires membrane-tethered APP cytoplasmic domains, rescued depletion. C-terminal fragments (CTFs) localized late endosome/lysosome-endoplasmic reticulum contacts; an excess of APP-CTFs herein reduced Ca2+ refilling from endoplasmic reticulum, promoting cholesterol accretion. Tonic regulation provides mechanistic explanation for their cellular toxicity: failure timely degrade sustains signaling, instigating dyshomeostasis, as prodromal AD. opposite substrates such Notch, which require intramembrane proteolysis initiate signaling.

Language: Английский

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