MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease

The accumulation of beta-amyloid protein (A beta) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar A beta plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful A beta and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). A beta aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on A beta accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased A beta load and microglial activation in the brain. The decrease in A beta load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce A beta load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of A beta from the brain. These findings also suggest that chronic inflammatory responses induced by A beta accumulation via the MyD88-dependent signaling pathway exacerbate beta-amyloidosis in AD. (Am J Pathol 2011. 179:1095-1103; DOI: 10.1016/j.ajpath.2011.05.045)