Loss of α7 nicotinic receptors enhances β-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease

Caterina M. Hernandez, Rakez Kayed, Hui Zheng, J. David Sweatt, Kelly T. Dineley

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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. α7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against β-amyloid (Aβ) toxicity and maintenance of the septohippocampal phenotype. We tested the role that α7 nAChRs perform in the etiology of early AD by genetically deleting the α7 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 α7 nAChR knock-out mice (A7KO) to render an animal with elevated Aβ in the absence of α7 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 Aβ that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomericAβ mayunderlie additional impairment ofA7KO-APPcognitive function. Thus, α7 nAChRsin 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 Aβ accumulation and oligomerization.

Original languageEnglish (US)
Pages (from-to)2442-2453
Number of pages12
JournalJournal of Neuroscience
Volume30
Issue number7
DOIs
StatePublished - Feb 17 2010

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Amyloid beta-Protein Precursor
Nicotinic Receptors
Amyloid
Alzheimer Disease
Pathology
Cholinergic Agents
Hippocampus
Maintenance
Phenotype
Cholinergic Neurons
Memory Disorders
Knockout Mice
Cognition
Transgenic Mice
Cognitive Dysfunction
Learning

ASJC Scopus subject areas

  • Neuroscience(all)

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Loss of α7 nicotinic receptors enhances β-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease. / Hernandez, Caterina M.; Kayed, Rakez; Zheng, Hui; Sweatt, J. David; Dineley, Kelly T.

In: Journal of Neuroscience, Vol. 30, No. 7, 17.02.2010, p. 2442-2453.

Research output: Contribution to journalArticle

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