Enriched environment enhances β‐adrenergic signaling to prevent microglia inflammation by amyloid‐β

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.

Activation of β2-Adrenoceptor Attenuates Sepsis-Induced Hippocampus-Dependent Cognitive Impairments by Reversing Neuroinflammation and Synaptic Abnormalities

“…The noradrenergic transmission system is known to be involved in various forms of learning and memory (O’Dell et al, 2015). Abnormalities of noradrenergic neurotransmission is associated with a number of cognitive disorders including AD (Xu et al, 2018), Down syndrome (Dang et al, 2014), and depression (Manczak et al, 2019). The levels of β2-AR is decreased in AD brain, presumably due to rapid internalization of β2-AR induced by soluble amyloid beta (Aβ) (Li et al, 2013; Takahashi et al, 2015).…”

“…Moreover, another animal study indicates that locally injection of the β2-AR antagonist into the hippocampal CA3 region impaired long-term contextual fear memory and water-maze spatial memory in mice (Zheng et al, 2015). In addition, numberous animal studies that β2-AR has potential antiinflammatory properties and plays an important role in maintaining the immunosuppressive environment within the central nervous system (CNS)(Agac et al, 2018; Xu et al, 2018). Thus, activation of β2-AR has been used for the treatment of many neurodegenerative diseases, such as Alzheimer’s disease (AD) (Wu et al, 2017), Rett syndrome (Mellios et al, 2014), and Parkinson’s disease (Abdelmotilib and West, 2017).…”

Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling

“…In addition, NE has been shown to reduce proinflammatory gene expression in microglia in various neurological disorders including stroke, pain, and neurodegeneration 37 . Particularly, NE can help resolve pathology in mouse models of AD by promoting microglial phagocytosis of Aβ and reducing Aβ-triggered inflammation 46,47 . However, microglia are also reported to be inappropriately activated in AD and mediate early synapse loss 48 .…”

Early-life stress facilitates the development of Alzheimer’s disease pathology via angiopathy

“…Fluorescence micrographs of the sections subjected to immunostaining procedures were captured and digitized with a FluoView® FV3000 confocal laser scanning microscope (Olympus., Tokyo, Japan). With the aim of quantifying the morphological change of microglia, skeleton analysis and particle analysis were performed by ImageJ (Fernández-Arjona et al, 2017;Xu et al, 2018).…”