Tauopathies: new perspectives and challenges

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Апрель 7, 2022

Abstract Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with range phenotypes that include cognitive/behavioral-disorders, movement disorders, language and non-specific amnestic symptoms in advanced age. Pathologically, be classified based on the predominant tau isoforms inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) blood-based biomarkers have potential to used as routine diagnostic strategy evaluation patients tauopathies. As strongly linked neuropathologically genetically protein abnormalities, there is growing interest pursuing tau-directed therapeutics for disorders. Here we synthesize emerging lessons from clinical, pathological, genetic, experimental studies toward unified concept these may accelerate therapeutics. Conclusions Since still untreatable diseases, efforts been made depict clinical pathological characteristics, identify biomarkers, elucidate underlying pathogenesis achieve early diagnosis develop disease-modifying therapies.

Язык: Английский

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Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Translational Neurodegeneration, Год журнала: 2022, Номер 11(1)

Опубликована: Март 18, 2022

Alzheimer's disease (AD) is the most common neurodegenerative in elderly worldwide. However, complexity of AD pathogenesis leads to discrepancies understanding this disease, and may be main reason for failure drug development. Fortunately, many ongoing preclinical clinical studies will continually open up avenues unravel mechanisms guide strategies diagnosis For example, immunotherapeutic targeting amyloid-β (Aβ) tau proteins were once deemed almost certainly effective treatment due excellent results. repeated failures trials on vaccines humanized anti-Aβ anti-tau monoclonal antibodies have resulted doubts strategy. Recently, a new antibody (Aducanumab) has been approved by US Food Drug Administration, which brings us back realization that immunotherapy Aβ still promising. Meanwhile, immunotherapies based other targets such as tau, microglia gut-brain axis are also under Further research needed clarify forms epitopes targeted improve accuracy effectiveness drugs. In review, we focus Aβ, their action AD. addition, present up-to-date advances future perspectives

Язык: Английский

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Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Июль 14, 2023

Abstract Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed aggregated β-amyloid (Aβ) hyperphosphorylated tau protein, respectively. In past few decades, disease-modifying therapy targeting Aβ has been focus AD drug development. Even though it is encouraging that two these drugs have recently received accelerated US Food Drug Administration approval for treatment, their efficacy or long-term safety controversial. Tau increasing attention as a potential therapeutic target, since evidence indicates pathology more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies pathological processes also linked deficits. Accumulating inflammation complex tight interplay pathology. Here, we review recent on interaction between pathology, focusing post-translational modification dissemination, neuroinflammatory responses, including glial cell activation inflammatory signaling pathways. Then, summarize latest clinical trials neuroinflammation. Sustained increased responses in cells neurons pivotal cellular drivers regulators exacerbation which further its worsening by aggravating responses. Unraveling precise mechanisms underlying relationship neuroinflammation will provide new insights into discovery translation targets other tau-related diseases (tauopathies). Targeting multiple pathologies precision strategies be crucial direction developing tauopathies.

Язык: Английский

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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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Tau-targeting therapies for Alzheimer disease: current status and future directions

Nature Reviews Neurology, Год журнала: 2023, Номер 19(12), С. 715 - 736

Опубликована: Окт. 24, 2023

Язык: Английский

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Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

International Journal of Alzheimer s Disease, Год журнала: 2022, Номер 2022, С. 1 - 10

Опубликована: Март 9, 2022

Background. Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer’s disease (AD). The this drug without confirmed significant clinical impact resulted in several debates. Objective. In narrative review, aducanumab approval-related controversy, drug’s pharmacokinetics and pharmacodynamic characteristics, evidence from efficacy safety trials aducanumab, implications approval, future directions management patients with AD are summarized. Methods. Using relevant keywords, Google Scholar, Web Science, MEDLINE databases manufacturer’s website were searched. Results. Infusion at higher dose modest slowing cognitive decline among impairment or early-onset dementia. however can cause amyloid-related imaging abnormalities. Due to on cognition, use will most likely be limited. manufacturer is required run an extended phase IIIb trial verify benefit drug. Access therapy requires careful selection periodic monitoring ensure optimal Conclusion. Despite limitations, first disease-modifying approved AD. Aducanumab addresses part pathogenesis AD; therefore, drugs act multiple needed. addition, search preventive strategies, validated plasma-based assays, newer AD, which effective, safe, convenient, affordable, vital.

Язык: Английский

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Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials

Cell, Год журнала: 2023, Номер 186(22), С. 4757 - 4772

Опубликована: Окт. 1, 2023

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.

Язык: Английский

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Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials

Molecular Psychiatry, Год журнала: 2023, Номер 28(6), С. 2197 - 2214

Опубликована: Июнь 1, 2023

Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was first pathological post-translational modification tau described Alzheimer's disease (AD), highlighting role PKs The therapeutic potential kinase inhibitors (PKIs)) and phosphatase 2 A (PP2A) activators AD has recently been explored several preclinical clinical studies variable outcomes. Where a number demonstrate visible reduction levels phospho-tau transgenic tauopathy models, no neurofibrillary lesions is observed. Amongst few PKIs PP2A that progressed trials, failed on efficacy front, only still unconfirmed positive trends. This suggests robust data needed unequivocally evaluate their efficacy. To this end, we take systematic look at results activators, evidence they provide regarding utility approach targeting modifying therapy.

Язык: Английский

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Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(12)

Опубликована: Июнь 14, 2023

Tauopathies are disorders associated with tau protein dysfunction and insoluble accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well nonclinical translational models, suggest that has a central pathologic role these disorders, historically thought to be primarily related gain toxic function. However, number tau-targeting therapies various mechanisms action have shown little promise clinical trials different tauopathies. We review what is known about biology, genetics, therapeutic been tested date. discuss possible reasons for failures therapies, such use imperfect models do not predict effects drug development; heterogeneity pathologies which may lead variable responses therapy; ineffective mechanisms, targeting wrong species or epitope. Innovative approaches can help address some difficulties plagued our field's development thus far. Despite limited success date, we continue refine understanding tau's pathogenic mechanism(s) neurodegenerative diseases, remain optimistic will eventually play treatment

Язык: Английский

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Cellular and pathological functions of tau

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 845 - 864

Опубликована: Июль 16, 2024

Язык: Английский

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