Targeting tau in Alzheimer’s and beyond: Insights into pathology and therapeutic strategies

Tauopathies encompass a group of approximately 20 neurodegenerative diseases characterized by the accumulation of the microtubule-associated protein tau in brain neurons. The pathogenesis of intracellular neurofibrillary tangles , a hallmark of tauopathies, is initiated by hyperphosphorylated tau protein isoforms that cause neuronal death and lead to diseases like Alzheimer’s, Parkinson’s disease, frontotemporal dementia , and other complex neurodegenerative diseases. Current applications of tau biomarkers, including imaging, cerebrospinal fluid, and blood-based assays, assist in the evaluation and diagnosis of tauopathies. Emerging research is providing various potential strategies to prevent cellular toxicity caused by tau aggregation such as: 1) suppressing toxic tau aggregation, 2) preventing post-translational modifications of tau, 3) stabilizing microtubules and 4) designing tau-directed immunogens. This review aims to discuss the role of tau in tauopathies along with neuropathological features of the different tauopathies and the new developments in treating tau aggregation with the therapeutics for treating and possibly preventing tauopathies. • Tau phosphorylation dynamics in physiological and pathological conditions contribute to neurodegeneration in tauopathies. • Neurofibrillary tangles of tau protein drive the pathology of diverse neurodegenerative diseases. • Tau's role in AD, FTDP-17, PSP, CTE, PiD, and corticobasal degeneration highlights its clinical significance. • Therapeutic strategies target tau aggregation, microtubule stability, PTMs, and tau immunotherapies.