Abstract
Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer’s disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.
Highlights
Tau is a microtubule-associated protein mainly found in the axonal part of neurons
Differential misfolding/hyperphosphorylation profile in human MAPT mutant carriers compared to sporadic Alzheimer’s disease (AD) We hypothesized that the mechanisms of tau deposition are different in sporadic tauopathies than when a mutation of MAPT gene is present
Since the discovery of tau protein as the principal component of neurofibrillary degeneration (NFD) [7, 26], around 20 pathologies involving aggregated tau were described with various time-courses, lesions
Summary
Tau is a microtubule-associated protein mainly found in the axonal part of neurons. Resulting from an alternative splicing mechanism, six major isoforms of tau coexist in the human brain with the presence of either 3 or 4 repeated sequences (named below as 3R-tau or 4R-tau) known as the microtubule-binding regions [8, 28]. Due to the molecular heterogeneity of tauopathies, different morphologies of lesions can be observed, with mainly flame-shaped neurofibrillary tangles in AD, argyrophilic grains and/or glial lesions in AGD or PSP and Pick bodies in Pick’s disease [39]. These lesions affect different part of the brain and the pathology evolves differently. Histopathological studies in some sporadic tauopathies such as AD [6, 15, 24], PSP [66, 69] and AGD [55] show that, for each disease, tau lesions appear progressively and hierarchically in the brain along anatomical connections The mechanisms underlying such evolution had remained unexplained for many years and are still poorly understood [60]. Our group and others recently showed that tau assemblies are transferred from cell-to-cell and, by being taken up by a second cell, seed the aggregation of endogenous tau leading to the propagation of tau lesions in the brain [13, 14, 19, 57, 65] reviewed in [48]
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