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

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

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

“…A convergence of recent genetic evidence identifies α7 nAChR as a potential modifier gene for schizophrenia and AD patients (39)(40)(41). Similarly, deleting the α7 nAChR gene leads to impairment of working/episodic-like memory (42) and alters the synaptic development and cognition in AD transgenic mice (43,44). α7 nAChRs thus are therapeutic targets for cognitive deficits in schizophrenia and AD (45)(46)(47)(48).…”

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…Analysis in early stage pre-plaque cognitive decline revealed neurodegeneration in A7KO-A␤PP hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of A␤ that was absent from all other genotypic groups [115].…”

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

“…33 Nevertheless, the mechanism of action of α7 nAChRs on AD appears to be very complex, 34 since both neuroprotection 35 and neurotoxicity 36 may be influenced by α7 nAChR activity. And, given the multifactorial nature of AD, the same might happen at the level of compounds used at present in its treatment.…”