Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid  -Protein Oligomers

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. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble A␤ oligomers (oA␤) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oA␤-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNF␣) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oA␤ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oA␤, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.

Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease

“…Exposure of mice to EE has a pivotal role for microglia activation and maintenance of adult neurogenesis because induced hippocampal neurogenesis by EE was associated with recruitment and activation of microglia cells (Ziv et al , ; Choi et al , ). The number of microglia was increased in WT mice as expected (Xu et al , ) but was unaffected in 5xFAD transgenic mice in accordance with the claim that the capability of microglia to respond to EE is dependent on the presence or absence of PS1 mutations (Choi et al , ). Only 5xFAD mice which had been injected with 5xFAD brain homogenate and subsequently exposed to EE revealed higher numbers of Iba1‐ and CD68‐positive cells despite the existence of PS1 mutations in those mice.…”

Prenatal Ethanol Exposure and Postnatal Environmental Intervention Alter Dopaminergic Neuron and Microglia Morphology in the Ventral Tegmental Area During Adulthood

“…Our results suggest a potential mechanism underlying the beneficial effects of postnatal environmental intervention on PE‐induced deficits is via the reduction in microglial activation–induced neuroinflammation. Indeed, environmental enrichment has been found to prevent and/or reduce neuroinflammation caused by various reasons, such as influenza (Jurgens and Johnson, ), traumatic brain injury (Benn et al, ), and amyloid beta (Ryan and Nolan, ; Xu et al, ). Environmental enrichment also reverses persistent neuroinflammation caused by adverse perinatal factors such as prenatal gram‐negative endotoxin lipopolysaccharide (LPS) exposure or neonatal hypoxia.…”

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

“…In healthy individuals, frontal lobe gray and white matter structure and connectivity have been associated with agerelated cognitive performance loss (Kievit et al, 2014;Serbruyns et al, 2016;Zhao et al, 2015) that may be associated with reduced myelination of the frontal lobe. Given the known benefits of cognitive training on myelination in healthy individuals Takeuchi et al, 2010), similar therapeutic interventions in HD gene-carriers may counteract the effects of age and thus positively influence HD pathogenesis before disease onset, akin to the disease-modifying effects of environmental enrichment in HD animal models (Dersi et al, 2016;Nithianantharajah and Hannan, 2006;Xu et al, 2016). Although this pattern of diffusivity correlated with global cognition in controls only, increased RD in the DLPFC-caudate tract specifically correlated with cognitive performance in both controls and HD.…”