Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum.

Pol Andrés-Benito,Joaquín Fernández-Irigoyen,José Antoni Del Rio,Isidro Ferrer,Mónica Jordán,Margarita Carmona,Enrique Santamaría

doi:10.3390/ijms23020718

Abstract

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.

Highlights

Neurodegenerative diseases with abnormal protein aggregates are characterized neuropathologically by the deposition of protein aggregates resulting mainly from aberrant post-translational modifications of primary constitutive elements of the nervous system.The term tauopathy covers heterogeneous diseases having in common the neuronal and glial deposition of abnormally phosphorylated species of tau protein, usually accompanied by other post-translational modifications in tau [1,2,3].Selective neuronal and glial vulnerability and progression are determinants in neurodegenerative diseases with abnormal protein aggregates [4,5]
Deposits occur in glial cells, and the morphology of glial inclusions appears to mimic the glial aggregates of the corresponding human tauopathies in inoculated transgenic mice expressing human tau or mutant human tau [10,11,12,13,14,15,16]
We speculated that host tau, as does inoculated tau, plays a role in the capacity for tau seeding and spreading [26]

Summary

Introduction

The term tauopathy covers heterogeneous diseases having in common the neuronal and glial deposition of abnormally phosphorylated species of tau protein, usually accompanied by other post-translational modifications in tau [1,2,3]. Selective neuronal and glial vulnerability and progression are determinants in neurodegenerative diseases with abnormal protein aggregates [4,5]. Several in vivo studies demonstrate the capacity for seeding and spreading of tau following intracerebral inoculation of transgenic mice expressing 4R human tau or mutant human tau. Tau seeding and spreading, occurs following intracerebral inoculation of similar tau aggregates in wild type mice (WT) and in transgenic WT mice [9,13,14,15]

Methods

Results

Conclusion