Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies

Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.