Unraveling the tau puzzle: a review of mechanistic targets and therapeutic interventions to prevent tau pathology in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by irreversible neural degeneration and cognitive decline. The prion-like propagation of the β-amyloid (Aβ) and tau proteins leads to the formation of protein plaques and, subsequently, neuronal dysfunction, contributing significantly to AD pathogenesis. Although effective AD treatments remain elusive, targeting tau protein aggregation has emerged as a promising therapeutic approach. However, recent anti-tau antibody trials have shown limited success in improving cognition, underscoring the need for a more advanced, multifaceted approach to address multiple mechanisms of tau pathology. This review examines the role of tau protein in the context of AD, with a particular focus on potential therapeutic interventions. Emphasis is placed on the modulation of tau protein expression, tau post-translational modifications and aggregation, receptor-mediated uptake and extracellular release pathways, neural inflammatory response pathways, intercellular organelle exchange, mitochondrial function, microtubule stability, and nuclear factor expression as critical intervention points. Despite the challenges faced in ongoing anti-tau clinical efforts, a comprehensive strategy targeting multiple pathways involved in tau pathology, by using either combinations of existing drugs or novel multitarget drugs, holds promise. By gaining a deeper understanding of the complex mechanisms underlying tau pathology, researchers can develop innovative therapeutic strategies to combat AD.