O4‐07‐01: IRAK‐M deletion promotes microglia‐mediated cerebral amyloid clearance in PSAPP mice

Background: Alzheimer disease (AD) is pathologically earmarked by deposition of Ab peptides as beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain innate immunity. Toll-like receptors (TLRs) are germline-encoded sensors of pathogens by cells of the innate immune system. TLRs transduce their signals through the serine/threonine IL1 receptor-associated kinase (IRAK). The IRAK family is chiefly comprised of kinases, which positively regulate TLR signaling, with the notable exception of the inhibitory kinase, IRAK-M. IRAK-M expression is exquisitely specific to cells of monocytic lineage, including microglia, and plays a critical role in the maintenance of innate immune homeostasis by dampening inflammation. Methods: We crossed mice deficient in IRAK-M (IRAKM-/-) with mice over expressing mutant human amyloid precursor protein, the PSAPP mouse model of cerebral amyloidosis. We then evaluated immune cell activation and cerebral Ab burden in age and sex-matched littermates from three groups: PSAPP-IRAK-M+/+, PSAPP-IRAK-M-/+, and PSAPP-IRAK-M-/mice. Results: Immunohistochemistry for reactive microglia disclosed statistically significant increased expression in PSAPPIRAK-M-/-vs. PSAPP-IRAK-M+/+mice in the hippocampus (up 42%, P<0.001), cerebral cortex (up 38%, P<0.001), and entorhinal cortex (up 42% P<0.001), brain regions classically associated with AD-type pathology in humans. Further, brain parenchymal Ab abundance was correspondingly attenuated in PSAPP-IRAK-M-/mice as measured by immunohistochemical and biochemical analyses of insoluble Ab1-40 and Ab1-42. Interestingly, confocal imaging of PSAPP-IRAK-M-/mouse brains revealed Ab colocalization with Lamp2+ lysosomes within microglia, suggesting a phagocytic mechanism of Ab removal in IRAK-M-/PSAPP mouse brains. Conclusions: Collectively, these data suggest that IRAK-M negatively regulates microglial Ab phagocytosis in a mouse model of cerebral amyloidosis. Disinhibition of IRAK-M may therefore represent a means to target microglial remodeling and clearance of cerebral amyloid pathology.