Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain

Abstract

Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.

Alzheimer’s disease as an inflammatory disease

“…Furthermore, tau can be phagocytosed by microglia (67). This finding would support the notion that impaired clearance of extracellular tau (by microglia) contributes to the spread of pathological tau, as shown in AD (68).…”

Stimulation of TLR4 Attenuates Alzheimer’s Disease–Related Symptoms and Pathology in Tau-Transgenic Mice

“…Aggregated Ab activates microglia through CD14/TLR2/TLR4-MyD88-kinase of NF-kB inhibitor (IKK) b signaling pathway (6)(7)(8)(9)(10). In p-Tau-induced AD pathogenesis, inflammatory activation might serve as a two-edged sword: on one side, certain inflammatory cytokines, such as IL-1b, promote phosphorylation and aggregation of Tau by activating p38a-MAPK in neurons (11)(12)(13). On the other side, microglial inflammatory activation potentially enhances neuronal macroautophagy (hereafter referred to as autophagy), and autophagy is an efficient way to degrade aggregated p-Tau proteins (14)(15)(16).…”

Different Roles of Microglia/Macrophage in Ischemic Stroke and Alzheimer's Disease

“…Activated microglia accelerates tau pathology and impairs working memory in an AD mouse model [26]. Consistently, depleting microglia dramatically suppressed the propagation of tau in the brain [27].…”

“…Although CX3CR1-/-is protective against neuronal loss in a mouse model of focal cerebral ischemia, it induces microglia activation, worsening tau pathology and impaired cognitive performance in a double transgenic mouse model that carries CX3CR1-/-and human tau protein (hTau-CX3CR1-/-) [26]. This microglia activation precedes tau aggregates since at six months of age there is minimal development of tau aggregates.…”