Cortical α7 Nicotinic Acetylcholine Receptor and β-Amyloid Levels in Early Alzheimer Disease

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Archives of neurology (Impact Factor: 7.42). 06/2009; 66(5):646-51. DOI: 10.1001/archneurol.2009.46
Source: PubMed


To examine alpha7 nicotinic acetylcholine receptor (nAChR) binding and beta-amyloid (Abeta) peptide load in superior frontal cortex (SFC) across clinical and neuropathological stages of Alzheimer disease (AD).
Quantitative measures of alpha7 nAChR by [(3)H]methyllycaconitine binding and Abeta concentration by enzyme-linked immunosorbent assay in SFC were compared across subjects with antemortem clinical classification of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem neuropathological diagnoses.
Academic medical center. Subjects Twenty-nine elderly retired clergy.
Quantitative measures of alpha7 nAChR binding and Abeta peptide concentration in SFC.
Higher concentrations of total Abeta peptide in SFC were associated with clinical diagnosis of mild to moderate AD (P = .02), lower Mini-Mental State Examination scores (P = .003), presence of cortical Abeta plaques (P = .02), and likelihood of AD diagnosis by the National Institute on Aging-Reagan criteria (P = .002). Increased alpha7 nAChR binding was associated with National Institute on Aging-Reagan diagnosis (P = .02) and, albeit weakly, the presence of cortical Abeta plaques (P = .08). There was no correlation between the 2 biochemical measures.
These observations suggest that during the clinical progression from normal cognition to neurodegenerative disease state, total Abeta peptide concentration increases while alpha7 nAChRs remain relatively stable in SFC. Regardless of subjects' clinical status, however, elevated alpha7 nAChR binding is associated with increased Abeta plaque pathology, supporting the hypothesis that cellular expression of these receptors may be upregulated selectively in Abeta plaque-burdened brain areas.

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    • "These different observations might reflect the changes in distribution and numbers of ␣7 nAChRs on neurons and astrocytes, respectively [33] [46]. Moreover, ␣7 nAChRs have been shown to increase with higher A␤ plaque load [45], especially in AD cases carrying APP swe mutations compared to sporadic AD cases [33]. The pathological A␤- ␣7 nAChR interactions could play a critical role in inducing incipient A␤ neurotoxicity mediated in part through the formation of A␤-␣7 nAChR complexes [19], and in turn disrupt receptor signaling and result in intracellular A␤ accumulation and synaptic dysfunction and contribute to the selective vulnerability of the cholinergic system in A␤-burdened brain regions [8] [16] [32]. "
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    ABSTRACT: The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-β (Aβ) assemblies bind to α7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Aβ by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Aβ. The α7 nAChR agonists varenicline and JN403, but not the α4β2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the α7 nAChR antagonists methyllycaconitine, α-bungarotoxin, and mecamylamine, but not by the α4β2 nAChR antagonist dihydro-β-erythroidine. Increases in 3H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter 3H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Aβ and α7 nAChRs in the brain, suggesting that treatment with α7 nAChR stimulatory drugs can modulate Aβ/α7 nAChR pathogenic signaling mechanisms in AD brain.
    Full-text · Article · Oct 2012 · Journal of Alzheimer's disease: JAD
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    • "This observation confirms earlier recent observations from our group demonstrating that brain regions with high fibrillar A␤ load also showed decreased density of nAChR binding sites (Kadir et al., 2011). Interestingly enough, the expression of ␣7 nAChRs ( 3 H-methyllycaconitine (MLA) binding ) has been shown to be stable in patients with mild cognitive impairment (MCI) as well as AD (Ikonomovic et al., 2009). Evidence from several studies suggest that different nAChR subtypes are highly sensitive to low concentrations of oligomeric A␤ 1– 42 , and that nAChR-mediated cell signaling is inhibited by interaction with A␤ (Liu et al., 2009). "
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    • "The majority of ACh effects on these neuron subtypes are directly mediated by postsynaptic nicotinic Ach receptors, in most cases of α7 subtype. In recent years, such receptor has gained interest because of its suggested putative role in the modulation of cognitive symptoms as well as in neurodegenerative processes383940. This has been revealed by experimental work on AD patients , in whom dopamine or serotoninergic transmission modulates the central cholinergic transmission in different brain areas41424344454647. "
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