Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

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.

Keywords: aggregation; membrane; tau; tauopathy; transmission.

FIGURE 1

Structure and membrane interaction of tau. (A) The isoforms of human tau. Tau is encoded by MAPT gene. Tau is mainly found as 6 isoforms in the adult human brain. Tau isoforms contain 0, 1 or 2 of N-terminal inserts (0N, 1N, or 2N) and 3 or 4 of C-terminal microtubule (MT)-binding-repeats (3R or 4R). The longest 2N4R tau (commonly referred to as tau40) consists of three functional domains including N-terminal acidic projection domain, proline-rich domain, and C-terminal MT-binding domain (MTBD). 2R- and 3R-region contain PHF6*- and PHF6-motif, respectively. K18 and K19 tau fragments are the MTBD fragments from 4R and 3R tau, respectively. (B) Schematic diagram of the tau-membrane interaction. Tau is a natively unstructured MT-associated protein that plays important roles in regulating microtubule dynamics, cellular trafficking, and signaling pathways. Tau undergoes a variety of post-translational modifications and conformational changes, leading to accumulation of tau aggregates, such as toxic oligomers and fibrils, under pathological conditions. Membrane lipids, such as sphingolipids and cholesterol, play critical roles in the tau-membrane interaction. The tau-membrane interaction may facilitate tau fibrillization through providing a platform favorable for tau nucleation.