Relevance of host tau in tau seeding and spreading in tauopathies

Abstract

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild‐type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age‐related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging‐related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl‐insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre‐tangles. A percentage of intracellular tau deposits co‐localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

“…However, no GAIs or GOIs, but only coiled bodies, are regularly seen in WT mice inoculated with sarkosyl-insoluble fractions of GGT linked to MAPT P301T mutation, sGGT, and GGT linked to MAPT K317M mutation in our study. The exception of a few bizarre oligodendroglial inclusions following inoculation of homogenates from MAPT K317M samples does not detract from the general concept that coiled bodies are the characteristic oligodendroglial phospho-tau inclusions in WT mice inoculated with homogenates from GGT and other tauopathies [36,37,41]. This suggests that host tau is crucial to recapitulate typical inclusions in human diseases.…”

“…Moreover, although GAIs and GOIs are typical of GGT, nothing is known about the functional alterations linked to the pathology of astrocytes and oligodendrocytes. Recent studies have shown the seeding capacity of GGT homogenates in vivo and in vitro [13,36,41]. However, little attention has been paid to the characteristics of tau deposits linked to the host tau.…”

“…Nerve fibres and coiled bodies were the only tau deposits in the corpus callosum following inoculation of homogenates from AD, primary age-related tauopathy (PART), ARTAG, GGT, PSP, Pick's disease (PiD), and frontotemporal lobar degeneration linked to MAPT P301L mutation (FTLD-P301L) [36]. Neurons and oligodendrocytes were the main targets following inoculation of sarkosyl-insoluble fractions of AD, PART, and ARTAG into the hippocampus of WT mice [37,41]. No GAIs, GOIs, or thorn-shaped astrocytes (characteristic of ARTAG) were seen following inoculation of GGT and ARTAG, respectively.…”

Astroglia and Tau: New Perspectives

“…Accordingly, it was shown that seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type using brain homogenates of ARTAG pathology (Ferrer et al, 2018). Thus, the host tau is also relevant for the seeding and spreading of tau pathology (Ferrer et al, 2020b).…”

Potential of Microfluidics and Lab-on-Chip Platforms to Improve Understanding of “prion-like” Protein Assembly and Behavior

“…In fact, the duration of the "lag-phase" is highly dependent not only on the monomer concentration and seed formation, but also on physical parameters as well as the presence of molecular chaperones. For example, when sarkosyl-insoluble fractions from AD patients or other tauopathies are analyzed in bulk experiments, the lag-phase cannot be clearly distinguished due to the high concentration of preformed fibrils and "amyloid seeds" (i.e., Ferrer et al, 2020b) in the sample and the curve is almost logarithmic. In fact, the time evolution of the "lag-phase" is also of interest for the characterization of some amyloids (i.e., MSA-derived synuclein vs. PD-derived synuclein) with different seeding as well as propagative properties (i.e., Shahnawaz et al, 2020).…”