The role of extracellular Tau in the spreading of neurofibrillary pathology

Abstract

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of Alzheimer's disease (AD) and several related disorders collectively known as tauopathies. Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of AD patients, tau pathology spreads following an anatomically defined pattern. Mounting evidence strongly suggests that accumulation of abnormal tau is mediated through spreading of seeds of the protein from cell to cell and point at the involvement of extracellular tau species as the main agent in the interneuronal propagation of neurofibrillary lesions and spreading of tau toxicity throughout different brain regions in these disorders. That would support the concept that pathology initiates in a very small part of the brain many years before becoming symptomatic, spreading progressively to the whole brain within 10-20 years. Understanding the precise molecular mechanism underlying tau propagation is crucial for the development of therapeutics for this devastating disorder. In this work, we will discuss recent research on the role of extracellular tau in the spreading of tau pathology, through synaptic and non-synaptic mechanisms.

Keywords: Alzheimer; exosomes; neurodegeneration; propagation; spreading; tau; tauopathies; vesicles.

Figure 1

Cell-to-Sources of extracellular tau and -cell spreading. The established view has long considered the presence of tau in the brain parenchyma or in the CSF as a consequence of tau protein being released after cell lysis. However, extracellular tau appears to result from a physiological process independent of cell death, as tau being can be released from cell lines and neurons via multiple pathways, either in naked form or vesicle-associated. In addition, tau misfolding in diseased brain leads to abnormal conformations of tau that can be taken up by surrounding neurons. Thus, pathological progression could involve transmission of tau protein through a prion-like mechanism resulting in neurodegeneration in susceptible brain regions.

Figure 2

A potential role for tau in synapsis during aging and AD. During AD, tau is hyperphosphorylated and mislocates to the axonal compartment. Furthermore, tau appears essential for Aβ-induced synaptotoxicity whereas extrasynaptic NR2B-containing NMDA receptors are required for tau-induced neurodegeneration. An increase of extrasynaptic receptors with aging and AD may also explain the progression of the disease.