Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer’s Disease

SIMPLE SUMMARY: The spatial progression of most Alzheimer’s Disease (AD) cases follows a well-defined route through the brain, yet research on the disease has yet to determine why this specific pattern of disease progression occurs. Recent developments have revealed that certain neurons are more vulnerable to AD stress than others, a concept which has since been termed “selective vulnerability”. Determining the cellular mechanisms that make certain neurons more vulnerable to disease could provide critical insights into how the disease leads to neurodegeneration and ultimately causes dementia. This review explores how modification of tau protein, a critical mediator of AD pathogenesis, may contribute to selective vulnerability and identifies key cellular components that may be involved at the earliest stages of disease progression. ABSTRACT: Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.