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

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. alpha 7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta-amyloid (A beta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha 7 nAChRs perform in the etiology of early AD by genetically deleting the alpha 7 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 alpha 7 nAChR knock-out mice (A7KO) to render an animal with elevated A beta in the absence of alpha 7 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 A beta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric A beta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha 7nAChRs 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 A beta accumulation and oligomerization.