Tau-mediated Mechanisms in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles of Tau. It is clinically accompanied by progressive cognitive impairment and behavioral deficits. Despite extensive AD research involving amyloid-β, pharmacological strategies targeting Aβ have shown limited clinical efficacy or adverse effects in clinical trials, while lecanemab and donanemab have shown to modestly but significantly slow cognitive decline in phase III clinical trials. However, the overall limited success of Aβ-directed therapies has shifted the attention to Tau protein. Therefore, understanding the pathology and pathogenesis of Tau in the contribution to AD is important for early diagnosis and effective treatment. Under physiological conditions, Tau stabilizes microtubules, axonal transport, and synaptic integrity. However, pathological post-translational modifications have been shown to disrupt Tau-microtubule interactions, promoting its aggregation and release into the extracellular region. Increasing evidence suggests the prion-like propagation of extracellular Tau drives the disease progression across the neuronal and glial cells leading to synaptic dysfunctions. The recent diagnostic approaches involving Tau-PET and Tau-based biofluid biomarkers have improved the detection of AD pathology. Therefore, effective clearance of Tau in AD requires understanding the molecular and cellular mechanisms regulating the pathological Tau degradation. This review explains the mechanistic contribution of extracellular Tau in AD pathogenesis and the cellular consequences. This will provide a foundation for understanding the influence of Tau on AD, the discovery of potential therapeutic strategies and new treatment methods for AD.