Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice

TLDR

Early microglial accumulation in AD promotes beta‑amyloid clearance, but persistent amyloid accumulation despite increased microglia suggests that clearance ability diminishes with age and disease progression. The study aimed to determine how aging and amyloid deposition affect microglial clearance capacity. The authors performed quantitative PCR on gene expression in microglia isolated from PS1‑APP mice at 1.5, 3, 8, and 14 months and from nontransgenic littermates. Old PS1‑APP microglia show markedly reduced expression of Abeta‑binding scavenger receptors and degrading enzymes, elevated IL‑1β and TNFα, and TNFα exposure further suppresses receptor expression and Abeta uptake, indicating that proinflammatory cytokines downregulate clearance pathways and promote amyloid accumulation, thereby contributing to neurodegeneration.

Abstract

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, 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 Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-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-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.