Human microglia, microglial LRRK2, and tau pathogenesis: a complex relationship

Abstract

AbstractBackgroundEmerging evidence indicates leucine‐rich repeat kinase 2 (LRRK2) may be involved in tau uptake and spread throughout the brain. Microglia, the brain‐resident phagocytes, become one of the highest LRRK2 expressing cells under inflammatory conditions. Rodent microglia were also shown capable of secreting seeding‐competent tau into the extracellular space. We set out to examine the contribution of human microglia and microglial LRRK2 to tau pathogenesis.MethodIsogenic LRRK2 wild‐type (WT) and knockout (KO) induced pluripotent stem cell (iPSC) lines, together with Parkinson’s disease (PD) patient‐isolated LRRK2 G2019S‐mutated iPSC lines were differentiated into an in‐vitro model of human microglia, and incubated with in‐house purified, endotoxin‐free, human recombinant 2N4R tau in monomeric or in vitro aggregated form to examine the cellular response.ResultMicroglia internalise recombinant monomeric and aggregated tau by overlapping but distinct mechanisms. RNA‐seq analysis was performed to reveal changes in microglial gene expression upon tau internalisation. We further identified LRP1 as one of the major microglia receptors mediating soluble tau entry, and LRRK2 bona‐fide substrates, Rab8a and Rab10, as the Rab GTPases involved in the downstream LRP1‐tau complex trafficking. The internalised soluble tau is readily degraded but intracellular clearance of tau aggregates is concentration‐ and incubation‐length dependent, and inversely associated with microglial tau secretion. Following tau fibril incubation, the intracellular non‐cleared tau and tau secreted by microglia, shows seeding competency, supporting the role for microglia in tau prion‐like spreading. Finally, we describe the influence of microglial LRRK2 on tau processing. Compared to LRRK2 WT, tau uptake and clearance is accelerated in G2019S microglia. However, tau fibrils processed by G2019S microglia, though reduced in the amount, template pathogenic conformation faster and more consistently onto naive tau substrate.ConclusionCollectively, we provide detailed characterisation of the response of human iPSC‐microglia to tau protein in its native and pathogenic form, and show that microglial LRRK2 influences tau processing in a complex way that warrants further investigation.