title: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.
abstract: Early Alzheimer's disease (AD) is marked by cholinergic hypofunction, neuronal marker loss, and decreased nicotinic acetylcholine receptor (nAChR) density from the cortex and hippocampus. alpha7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta-amyloid (Abeta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha7 nAChRs perform in the etiology of early AD by genetically deleting the alpha7 nAChR subunit from the Tg2576 mouse model for AD and assessing animals for cognitive function and septohippocampal integrity. Thus, Tg2576 mice transgenic for mutant human amyloid precursor protein (APP) were crossed with alpha7 nAChR knock-out mice (A7KO) to render an animal with elevated Abeta in the absence of alpha7 nAChRs (A7KO-APP). We found that learning and memory deficits seen in 5-month-old APP mice are more severe in the A7KO-APP animals. Analyses of animals in early-stage preplaque cognitive decline revealed signs of neurodegeneration in A7KO-APP hippocampus as well as loss of cholinergic functionality in the basal forebrain and hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of Abeta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric Abeta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha7 nAChRs in a mouse model for early-stage AD appear to serve a neuroprotective role through maintenance of the septohippocampal cholinergic phenotype and preservation of hippocampal integrity possibly through influences on Abeta accumulation and oligomerization.
authors.affiliation: Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051839:NFI Transcription Factors / Q000378:metabolism; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010364:Pattern Recognition, Visual / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000378:metabolism; D012153:Retention, Psychology / Q000502:physiology; D020665:Septum of Brain / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C077305:CTF-1 transcription factor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D051839:NFI Transcription Factors; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002795:Choline O-Acetyltransferase