Jean-Noel Octave, Belgium
Catholic University of Louvain Institute of NeuroscienceAuthor Of 1 Presentation
MICROGLIAL CONTRIBUTION IN AMYLOID-FACILITATED TAU-PATHOLOGY AND DOWNSTREAM NEURODEGENERATION ALONG THE A/T/N AXIS
Abstract
Aims
Brains of AD patients are characterized by the presence of amyloid pathology, Tau-pathology and neurodegeneration, referred to as A-, T- and N-pathology, respectively. AD brains are also characterized by microgliosis, which may contribute differently at different stages of the AD process. In this work, we aimed to identify microglial phenotypes and the active contribution of microglia on amyloid-facilitated Tau-pathology and subsequent Tau-induced neurodegeneration in an in vivo model.
Methods
To assess the effect of amyloid pathology on Tau-seeding, we performed Tau-seeding in the presence and absence of amyloid pathology (in TauP301S.5xFAD mice (F+/T+) and parental TauP301S mice) at 4 months. Tau-seeded Tau-pathology and its propagation were significantly increased in the presence of amyloid pathology 3 months post-seeding. Strikingly, significant hippocampal and cortical atrophy were detected only in the presence of amyloid pathology, recapitulating A/T/N pathology. To assess microglial contributions in Tau-pathology and neurodegeneration in the presence of amyloid pathology we used microglial depletion by CSF1R inhibition (PLX3397), and identified the microglial phenotypes using single cell sequencing.
Results
Tau-seeded Tau-pathology downstream of amyloid pathology was significantly decreased in Tau-seeded mice by PLX3397 treatment. Similarly, in PLX3397 treated mice, attenuated cerebral atrophy was observed. Analysis of microglial phenotypes is currently ongoing.
Conclusions
We here demonstrate that microglia actively contribute to Tau-pathology and Tau-induced neurodegeneration in the presence of amyloid pathology in an in vivo model recapitulating combined ATN pathologies.