Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (A beta)before formation of senile plaques. However, persistent A beta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear A beta may decrease with age and progression of AD pathology. To determine the effects of aging and A beta deposition on microglial ability to clear A beta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the A beta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the A beta-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1 beta(interleukin-1 beta) and tumor necrosis factor alpha(TNF alpha), suggesting that there is an inverse correlation between cytokine production and A beta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNF alpha decreased the expression of SRA and CD36 and reduced A beta uptake. Our data indicate that, although early microglial recruitment promotes A beta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to A beta deposition downregulate genes involved in A beta clearance and promote A beta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.