RESUMO
Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid ß (Aß) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1ß, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aß deposits, which might facilitate Aß clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Cell culture experiments further showed that treatments with interleukin-1ß decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aß clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice.