The Fate of Tau Aggregates Between Clearance and Transmission

Abstract

Neuronal accumulation of mis-folded tau is the pathological hallmark of multiple neurodegenerative disorders, including Alzheimer’s disease. Distinct from amyloid plaques, which appear simultaneously throughout the brain, tau pathology develops first in a specific brain region and then propagates to neuroanatomically connected brain regions, exacerbating the disease. Due to the implication in disease progression, prevention of tau transmission is recognized as an important therapeutic strategy that can halt disease progression in the brain. Recently, accumulating studies have demonstrated diverse cellular mechanisms associated with cell-to-cell transmission of tau. Once transmitted, mis-folded tau species act as a prion-like seed for native tau aggregation in the recipient neuron. In this review, we summarize the diverse cellular mechanisms associated with the secretion and uptake of tau, and highlight tau-trafficking receptors, which mediate tau clearance or cell-to-cell tau transmission.

Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia

“…In the present study, we investigated the roles of CR3 and CR4 in the clearance of extracellular tau by microglia. Because mounting evidence has shown that extracellular tau exist in various forms, such as monomers and aggregates, mostly as vesicle-free forms [17][18][19][20][21][22][23][24][25][26][27][28][29], we focused on the clearance of vesicle-free tau monomers and fibrils through these two complement receptors by microglial cells. Here, we provide evidence that CR4 but not CR3 is a phagocytic receptor specific for tau fibrils that mediates the clearance of extracellular tau fibrils by BV2 microglial cells as well as primary microglia.…”

“…Although the precise molecular mechanisms underlying the propagation of tau pathology remain elusive, several pathways have been suggested for the secretion of tau, such as vesicle-mediated pathways through exosomes [16], ectosomes [17] and vesicle-free direct translocation across the plasma membrane [18,19]. Although the amount and types of extracellular tau vary depending on the disease status, different forms of tau, such as monomers and aggregates, exist in the extracellular space mostly in vesicle-free forms [17][18][19][20][21][22][23][24][25][26][27][28][29]. Besides mediating cell-to-cell transmission, extracellular tau is toxic to neurons by inducing neuritic degeneration, perturbing axonal transport and impairing memory [30][31][32][33][34][35][36][37][38][39][40].…”

“…Activated microglia can also contribute to the tau propagation by transmitting tau seeds via an exosome-mediated pathway [20,49,50]. Conversely, accumulating evidence from several in vivo and in vitro studies suggests that microglia can restrict tau spreading by internalizing and degrading extracellular tau proteins through multiple pathways, such as phagocytosis, macropinocytosis, and micropinocytosis [21,43,51]. Although recent studies showed that Fcand C-X3-C motif chemokine receptor 1 (CX3CR1) mediate antibody-mediated clearance of extracellular tau aggregates and soluble tau monomers by microglia, respectively [52][53][54], the detailed mechanisms underlying tau clearance by microglia remain largely unknown.…”