Abstract
Abnormal accumulation of misfolded tau aggregates is a pathological hallmark of various tauopathies including Alzheimer’s disease (AD). Although tau is a cytosolic microtubule-associated protein enriched in neurons, it is also found in extracellular milieu, such as interstitial fluid, cerebrospinal fluid, and blood. Accumulating evidence showed that pathological tau spreads along anatomically connected areas in the brain through intercellular transmission and templated misfolding, thereby inducing neurodegeneration and cognitive dysfunction. In line with this, the spatiotemporal spreading of tau pathology is closely correlated with cognitive decline in AD patients. Although the secretion and uptake of tau involve multiple different pathways depending on tau species and cell types, a growing body of evidence suggested that tau is largely secreted in a vesicle-free forms. In this regard, the interaction of vesicle-free tau with membrane is gaining growing attention due to its importance for both of tau secretion and uptake as well as aggregation. Here, we review the recent literature on the mechanisms of the tau-membrane interaction and highlights the roles of lipids and proteins at the membrane in the tau-membrane interaction as well as tau aggregation.
Highlights
Tau is a microtubule (MT)-associated protein that plays important roles in regulating MT dynamics and cellular trafficking as well as signaling pathways (Morris et al, 2011; Barbier et al, 2019)
Doktorova et al (2017) demonstrated that the presence of cholesterol in the membrane enhances the interaction of retroviral structural protein Gag to the phosphatidylserinerich clusters of the membrane by increasing lipid packing and membrane surface charge density. These findings suggest that cholesterol and sphingomyelin-dependent membrane microdomains play a critical role in tau secretion by mediating recruitment of tau to the cytosolic leaflet of the plasma membrane (PM)
Elucidating the roles of the tau-membrane interaction are critical for understanding of the mechanisms of tau fibrillization, intercellular transmission, and dysfunction of biological processes associated with tauopathies
Summary
Tau is a microtubule (MT)-associated protein that plays important roles in regulating MT dynamics and cellular trafficking as well as signaling pathways (Morris et al, 2011; Barbier et al, 2019). Accumulating evidence demonstrated that tau interacts with the membrane through binding to several different membrane proteins and thereby induce cellular dysfunctions and propagation of tauopathies. Takahashi et al (2015) demonstrated that 1N4R and 1N3R tau fibrils, but not monomers, binds to APP through its N-terminal extracellular region and induces intracellular templated misfolding in SH-SY5Y cells, suggesting that R2 domain does not critically mediate the interaction of tau fibrils with APP.
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