title: Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers.
abstract: A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. sli11@partners.org
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Jin
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Koeglsperger
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004777:Environment; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D018408:Patch-Clamp Techniques; D010805:Physical Conditioning, Animal; D018091:Receptors, AMPA / Q000235:genetics / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D016229:Amyloid beta-Peptides; D018091:Receptors, AMPA; D018343:Receptors, Adrenergic, beta-2