The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease

Abstract

BackgroundMisfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that tau pathology spreads inter-neuronally via misfolded tau “seeds.” Previous research has focused on neurons as the source of these tau seeds. However, recent studies as well as the data contained herein suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology.MethodsPrimary adult microglia were isolated from human AD cases and the rTg4510 tauopathy mouse model and used for analysis of gene expression, tau protein by Simoa technology, and quantification of tau seeding using a highly sensitive fluorescence resonance energy transfer (FRET) biosensing cell line for tau seeding and aggregation.ResultsHere, we show that microglia isolated from both human tauopathy and AD cases and the rTg4510 tauopathy mouse model stably contain tau seeds, despite not synthesizing any tau. Microglia releases these tau seeds in vitro into their conditioned media (CM). This suggests that microglia have taken up tau but are incapable of entirely neutralizing its seeding activity. Indeed, when in vitro microglia are given media containing tau seeds, they reduce (but do not eliminate) tau seeding. When microglia are treated with inflammagens such as lipopolysaccharide (LPS), interleukin-1β (IL1β), tumor necrosis factor α (TNFα), or amyloid-β, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own.ConclusionsOverall, these data suggest that microglia have a complex role: they are capable of taking up and breaking down seed competent tau, but do so inefficiently and could therefore potentially play a role in the spread of tau pathology.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1309-z) contains supplementary material, which is available to authorized users.

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

“…Activated microglia engulf patho-proteins containing neurons flagging phosphatidylserine signals [76] and degrade via lysosomal machinery [58]. But, the failure of proper proteolysis can lead to the excretion of cleaved peptides, which acts as seed entities for further aggregation within healthy neurons [77]. In our study, we found the phagocytosis of extracellular Tau oligomers and adherence of high molecular weight Tau aggregates onto N9 microglial cells, indicating the initiation of active internalization and clearance.…”

Mechanisms of secretion and spreading of pathological tau protein

“…As microglia do not normally express tau, this indicates that microglia had engulfed tau aggregates from the extracellular space, or as a part of engulfed debris from dead neurons. It has been shown that microglia have the ability to internalize tau to degrade it [219][220][221]. However, when the amount of aggregating protein surpasses the degradation capabilities of microglia, toxic tau aggregates appear in the cytoplasm and promote microglial dysfunction [222].…”

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

“…After tau seeds enter the neuron, they can leak via damaged vesicles into the cytosol and seed physiological monomers to propagate the pathological process (59,60). Additionally, microglia and astrocytes can phagocytose (61)(62)(63). The process of tau spreading is now hypothesized to underlie the progression of tau pathology throughout the brain (Figure 3).…”