Enriched environment enhances β‐adrenergic signaling to prevent microglia inflammation by amyloid‐β. Issue 9 (9th August 2018)

• Record Type: Journal Article
• Authors: Xu, Huixin; Rajsombath, Molly M; Weikop, Pia; Selkoe, Dennis J
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 9(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-08-09
• Subjects: Alzheimer's disease -- environmental enrichment -- microglia -- neuroinflammation -- β‐adrenergic signaling; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201808931
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti‐inflammatory protection of brain microglia against soluble oligomers of human amyloid β‐protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β‐adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β‐adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ‐induced inflammation as did mice in EE. Conversely, mice in EE fed the β‐adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2‐adrenergic receptors showed no protection of microglia by EE. In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial‐specific analysis of β2‐adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE. Thus, enhanced β‐adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers in vivo . Synopsis: Environmental enrichment (EE) may provide protection against features of Alzheimer's disease but its impact on innate immunity lacks mechanistic understanding. EE in mice is shown to protect microglia from inflammation by amyloid beta‐protein oligomers via enhanced beta‐adrenergic signaling in vivo . Pharmacological agonism and antagonism of beta‐adrenergic signaling respectively mimics or blocks the benefits of EE against Abeta in wild‐type mice. Mice lacking beta‐adrenergic receptors fail to experience anti‐Abeta microglial protection from EE. Microglial beta‐adrenergic signaling in the dentate gyrus is disrupted by Abeta and rescued by EE. The ability of beta‐adrenergic signaling to neutralize oAbeta‐induced microglia inflammation is partially cAMP‐dependent. Abstract : Environmental enrichment (EE) may provide protection against features of Alzheimer's disease but its impact on innate immunity lacks mechanistic understanding. EE in mice is shown to protect microglia from inflammation by amyloid beta‐protein oligomers via enhanced beta‐adrenergic signaling in vivo .