The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration.

Mar Puigdellívol,Jacob M Dundee,Katryna Pampuščenko,Maria Grazia Spillantini,Hugh N Nuthall,Vilmante Borutaite,Jack H Brelstaff,David H Allendorf,Anna Vilalta,Jeffrey Y Lee,Stefan Milde,Guy C Brown,Tom O.J Cockram

doi:10.1016/j.celrep.2021.110148

Abstract

SummaryMicroglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The microglial P2Y6 receptor (P2Y6R) – activated by extracellular UDP released by stressed neurons – is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal and memory loss, and this is all prevented by knockout of P2Y6R. In a chronic tau model of neurodegeneration (P301S TAU mice), P2Y6R knockout prevented TAU-induced neuronal and memory loss. In vitro, P2Y6R knockout blocked microglial phagocytosis of live but not dead targets and reduced tau-, Aβ-, and UDP-induced neuronal loss in glial-neuronal cultures. Thus, the P2Y6 receptor appears to mediate Aβ- and tau-induced neuronal and memory loss via microglial phagocytosis of neurons, suggesting that blocking this receptor may be beneficial in the treatment of neurodegenerative diseases.

Highlights

There is growing evidence that excessive phagocytosis of neurons and/or neuronal parts by microglia may contribute to the brain pathology of neurodegenerative diseases, including Alzheimer’s disease (AD) (Hong et al, 2016; Paolicelli et al, 2017; Butler et al, 2021), as well as aging (Shi et al, 2015; LinnartzGerlach et al, 2019)
We previously found that an inhibitor of P2Y6 receptor (P2Y6R), N,N’’-1,4-Butanediylbis[N’-(3-isothiocyanatophenyl)thiourea (MRS2578), prevented neuronal loss induced by lipopolysaccharide (LPS) injected into brain or cell cultures of wild-type (WT) animals (Neher et al, 2014), but it remains unclear (1) whether this was mediated by P2Y6R, (2) whether P2Y6R inhibition is beneficial or detrimental, (3) whether P2Y6R mediates the phagocytosis of alive or dead cells/targets, and (4) whether neurodegeneration is mediated by P2Y6R-activated microglial phagocytosis
P2ry6 knockout in mice prevents amyloid beta (Ab)-induced microglial phagocytosis of neurons, neuronal loss, and memory deficits in vivo To determine whether P2Y6R is involved in neurodegeneration, we used an acute amyloid model of AD (Prediger et al, 2007), known to feature excessive microglial phagocytosis (Hong et al, 2016)

Summary

Introduction

There is growing evidence that excessive phagocytosis of neurons and/or neuronal parts by microglia may contribute to the brain pathology of neurodegenerative diseases, including Alzheimer’s disease (AD) (Hong et al, 2016; Paolicelli et al, 2017; Butler et al, 2021), as well as aging (Shi et al, 2015; LinnartzGerlach et al, 2019). We and others have shown that microglia can cause neuronal loss and death by phagocytosis of stressed-but-viable neurons in some conditions (Brown and Neher, 2014; Neher et al, 2011; Brelstaff et al, 2018), but whether this contributes to neurodegeneration is unknown (Fricker et al, 2018). Neuronal loss occurs relatively late in AD but correlates well with dementia (Andrade-Moraes et al, 2013). This suggests the possibility that blocking such neuronal loss (for example, by blocking microglial phagocytosis of stressed neurons) may stop or delay disease progression, even after diagnosis

Methods

Results

Discussion

Conclusion