Converging pathologies in neurodegeneration: the mechanistic interplay between α-Synuclein and Tau in Alzheimer's and Parkinson's.

Abstract

Alzheimer's and Parkinson's disease are the most prevalent neurodegenerative disorders globally, each characterized by distinct pathological hallmarks; primarily tau neurofibrillary tangles and amyloid-beta plaques in AD, and alpha-synuclein (α-Syn) Lewy bodies in PD. However, evidence suggests a complex interplay between these proteins, particularly α-Syn and tau, which may contribute to the progression of both diseases. Recent observations demonstrate the co-occurrence of α-Syn and tau pathologies in both AD and PD patients. At the molecular level, both proteins exhibit prion-like propagation properties and can undergo cross-seeding, where one misfolded protein species induces the misfolding, aggregation of the other and increasing neurotoxicity. These proteins also share common post-translational modifications, cellular clearance mechanisms, and are influenced by similar microenvironmental factors that favor protein aggregation. This review explores the potential mechanisms by which α-Syn in PD may influence tau pathology, potentially exacerbating AD like disease progression that may potentially contribute to cognitive decline in PD. This review also delves into the underlying molecular pathways, such as prion-like propagation, cross-seeding, and inflammatory responses that could mediate this interaction, leading to enhanced neurodegeneration in comorbid cases. Further, various clinical implications of proteins' interplay, relevance to mixed neurodegenerative phenotypes, and potential therapeutic strategies targeting both α-Syn and tau pathologies have also been discussed in this manuscript.