Brelstaff, Jack H

Ghetti, Bernardino

Katsinelos, Taxiarchis

Mason, Matthew

McEwan, William A

Spillantini, Maria Grazia

Tolkovsky, Aviva M

English

PubMed

Apollo (Cambridge)

Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates.

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau mice due to neuronal tau aggregate-induced exposure of the “eat me” signal phosphatidylserine. Here, we show that after phagocytosing tau aggregate-bearing neurons, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia express a senescence-like phenotype, demonstrated by acidic β-galactosidase activity, secretion of paracrine senescence-associated cytokines, and maturation of matrix remodeling enzymes, results that are corroborated in P301S mouse brains and ex vivo brain slices. In particular, the nuclear factor κB–dependent activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in brains from patients with tauopathy. These data show that microglia that have been activated to ingest live tau aggregates-bearing neurons behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.This work was supported by an Alzheimer’s Research UK fellowship ARUK-
RF2017A-4 , and grants from the European Union (EU/EFPIA/Innovative Medicines  Initiative 2, Joint Undertaking n116060, IMPRIND , the Wellcome Trust and a Royal Society Sir Henry Dale Fellowship Grant Number 206248/Z/17/Z,, the UKDRI (funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK), the Alzheimer's Society, a iCase BBSRC and Eli Lilly studentship #G103374 .  Department of Pathology and Laboratory Medicine, Indiana University School of Medicine and NIH grant P30-AG010133. The Cambridge Brain Bank is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre

Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates.

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Apollo (Cambridge)

Apollo (Cambridge)