The Regulatory Effects of Environmental Enrichment on Microglia in Health and in Alzheimer’s Disease Model Systems

Abstract

Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer’s disease (AD). Environmental enrichment (EE) is well-documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain’s innate immune system. This thesis project first reported that prolonged exposure of wild-type mice to EE significantly alters microglial density and branching complexity in the dentate gyrus of hippocampus. Then, in wild-type mice injected intraventricularly with soluble Ab oligomers (oAb) from hAPP-expressing cultured cells, EE rescued several morphological features of microglial inflammation and consistently prevented oAb-mediated mRNA changes in multiple inflammatory genes, both in vivo and in primary microglia cultured from the EE-treated mice. Microdialysis in behaving mice combined with high sensitivity ELISAs confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFa) identified by the mRNA analysis. Moreover, EE consistently rescued the effects of ventricular injection of oAb extracted directly from AD human cerebral cortex. The protective effects of EE were also observed in aged mice. Mechanistically, the noradrenergic signaling pathway of microglia was identified as one key mediator of EE’s regulatory effects on microglia by using a combination of pharmacological treatments of mice and biochemical quantification of brain norepinephrine by high performance liquid chromatography. In summary, I show that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human Ab oligomers, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain’s innate immune system. The protection is imposed in part through EE’s regulation of noradrenergic signaling by microglia.