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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Cellular and pathological functions of tau

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

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Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113761 - 113761

Published: Feb. 1, 2024

Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, together produce β-peptide (Aβ). Nevertheless, whether Aβ is primary driver remains controversial. We report here FAD mutations disrupt initial proteolytic events multistep processing APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals a mimetic traps γ-secretase during transition state, this structure aligns with activated enzyme-substrate complex captured molecular dynamics simulations. In silico simulations cellulo fluorescence support stabilization complexes mutations. Neuronal expression and/or presenilin-1 Caenorhabditis elegans leads to synaptic loss only FAD-mutant transgenes. Designed stabilize block production likewise led loss. Collectively, these findings implicate stalled process—not products—of cleavage substrates pathogenesis.

Language: Английский

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Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14499 - 14499

Published: Sept. 24, 2023

Over the past 30 years, majority of (pre)clinical efforts to find an effective therapy for Alzheimer’s disease (AD) focused on clearing β-amyloid peptide (Aβ) from brain since, according amyloid cascade hypothesis, was (and it is still considered by many) pathogenic determinant this neurodegenerative disorder. However, as reviewed in article, results numerous clinical trials that have tested anti-Aβ therapies date indicate plays a minor role pathogenesis AD. Indeed, even Aducanumab and Lecanemab, two antibodies recently approved FDA AD therapy, well Donanemab showed limited efficacy cognitive parameters phase III trials, despite their capability markedly lowering Aβ load. Furthermore, preclinical evidence demonstrates possesses several physiological functions, including memory formation, suggesting may part be due loss function peptide. Finally, generally accepted could result many molecular dysfunctions, therefore, if we keep chasing only Aβ, means cannot see forest trees.

Language: Английский

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The Role of TNF-α in Alzheimer’s Disease: A Narrative Review

Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 54 - 54

Published: Dec. 26, 2023

This review analyzes the role of TNF-α and its increase in biological fluids mild cognitive impairment, Alzheimer’s disease (AD). The potential inhibition with pharmacological strategies paves way for preventing AD improving function people at risk dementia. We conducted a narrative to characterize evidence relation involvement possible therapeutic inhibition. Several studies report that patients RA systemic inflammatory diseases treated blocking agents reduce probability emerging dementia compared general population. Animal model also showed interesting results are discussed. An increasing amount basic scientific data clinical underscore importance processes subsequent glial activation pathogenesis AD. targeted therapy is biologically plausible approach cognition preservation further trials necessary investigate benefits populations developing

Language: Английский

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Evolving therapeutic interventions for the management and treatment of Alzheimer’s disease

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 95, P. 102229 - 102229

Published: Feb. 15, 2024

Language: Английский

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Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3892 - 3892

Published: March 31, 2024

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that protein amyloid-beta cause of disease. Two antibodies, aducanumab and lecanemab, have been approved by U.S. Food Drug Administration, while a third, donanemab, under review. main argument FDA approvals presumed therapy-induced removal cerebral deposits. Lecanemab donanemab are also thought to some statistical delay in determination cognitive decline. However, clinical efficacy less than with conventional treatment, selection amyloid-positive trial patients non-specific amyloid-PET imaging, uncertain amyloids trials cast doubt on this anti-Alzheimer's antibody therapy hence hypothesis, calling more thorough investigation negative impact type brain.

Language: Английский

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Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(2), P. 536 - 536

Published: Jan. 17, 2024

Background: The concept of Alzheimer disease (AD)—since its histological discovery by to the present day—has undergone substantial modifications. Methods: We conducted a classical narrative review this field with bibliography selection (giving preference Medline best match). Results: following subjects are reviewed and discussed: Alzheimer’s discovery, Kraepelin’s creation new that was rare condition until 1970′s, growing interest investment in AD as major killer society large elderly population second half 20th century, consolidation clinicopathological model, modern nosology based on dominant amyloid hypothesis among many others. In 21st development biomarkers has supported novel biological definition AD, although proposed therapies have failed cure disease. incidence dementia/AD shown decrease affluent countries (possibly due control risk factors), mixed dementia been established most frequent etiology oldest old. Conclusions: current lacks unanimity. Many hypotheses attempt explain complex physiopathology entwined aging, cascade yielded poor therapeutic results. reduction appears promising but it should be confirmed future. A reevaluation is also necessary.

Language: Английский

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Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 99, P. 102348 - 102348

Published: June 1, 2024

Language: Английский

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Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4323 - 4323

Published: April 13, 2024

Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death nervous system's cells. The diagnosis is challenging, especially in early stages, due to no specific clinical signs symptoms. In this context, laboratory medicine could support clinicians detecting differentiating NDs. Indeed, biomarkers indicate pathological mechanisms underpinning ideal biofluid for NDs cerebrospinal fluid (CSF), which has limitations, hampering its widespread use practice. However, intensive efforts are underway introduce high-sensitivity analytical methods detect ND alternative nonivasive biofluid, such as blood or saliva. This study presents an overview molecular currently used For some diseases, Alzheimer's disease multiple sclerosis, well established recommended guidelines. most NDs, research ongoing identify reliable biomarkers, consensus yet been achieved.

Language: Английский

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