title: GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability.
abstract: Why certain diseases primarily affect one specific neuronal subtype rather than another is a puzzle whose solution underlies the development of specific therapies. Selective basal forebrain cholinergic (BFC) neurodegeneration participates in cognitive impairment in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. Here, we report the first recapitulation of the selective BFC neuronal loss that is typical of human AD in a mouse model termed GAP. We created GAP mice by crossing Tg2576 mice that over-express the Swedish mutant human β-amyloid precursor protein gene with G protein-coupled receptor kinase-5 (GRK5) knockout mice. This doubly defective mouse displayed significant BFC neuronal loss at 18 months of age, which was not observed in either of the singly defective parent strains or in the wild type. Along with other supporting evidence, we propose that GRK5 deficiency selectively renders BFC neurons more vulnerable to degeneration.
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Minchao
authors.initials: M
authors.lastname: He
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Singh
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Shaowu
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.|Department of Cognitive Sciences, Beijing Institute of Basic Medical Sciences, Beijing, 100850, P.R. China.
authors.forename: XueFeng
authors.initials: X
authors.lastname: Ding
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
authors.forename: Longxuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.|Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, Duke Univ. Med. Center, Durham, NC 27710, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: The Johnnie B. Byrd Alzheimer's Center &Research Institute, Tampa, FL 33620, USA.|Deptment of Molecular Pharmacology &Physiology, University of South Florida, Tampa, FL 33620, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Neurology, University of Kansas Medical College, Kansas City, KS 66170, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical College, Kansas City, KS 66170, USA.|The University of Kansas Alzheimer's Disease Center, Kansas City, KS 66160, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Burns
authors.affiliation: Department of Neurology, University of Kansas Medical College, Kansas City, KS 66170, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical College, Kansas City, KS 66170, USA.|The University of Kansas Alzheimer's Disease Center, Kansas City, KS 66160, USA.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.affiliation: Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, MO 64128, USA.|Department of Neurology, University of Kansas Medical College, Kansas City, KS 66170, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical College, Kansas City, KS 66170, USA.|The University of Kansas Alzheimer's Disease Center, Kansas City, KS 66160, USA.
authors.forename: William Z
authors.initials: WZ
authors.lastname: Suo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D066187:Basal Forebrain / Q000473:pathology*; D059329:Cholinergic Neurons / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000172:deficiency*; D006801:Humans; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse