title: Aβ selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer's disease.
abstract: Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer's disease (AD) and is thought to be responsible for the cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR-mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving cofilin-regulated actin dynamics. In BF cholinergic neurons, β-amyloid (Aβ) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75(NTR)-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by Aβ in BF cholinergic neurons. It provides a potential basis for the Aβ-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214.
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, Veterans Administration Western New York Healthcare System, Buffalo, New York 14215, and.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214.
authors.forename: Luye
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, Veterans Administration Western New York Healthcare System, Buffalo, New York 14215, and Department of Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing Institute for Brain Disorders, Beijing 100069, China zhenyan@buffalo.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D016202:N-Methylaspartate / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000473:pathology*; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D016202:N-Methylaspartate; D002795:Choline O-Acetyltransferase
keywords: NMDA receptor; actin; basal forebrain; beta-amyloid; cholinergic; mGluR