Amyloid Peptide Aβ_1‐42 Binds Selectively and with Picomolar Affinity to α7 Nicotinic Acetylcholine Receptors

Abstract

Abstract:We have recently reported evidence that a very high affinity interaction between the ␤-amyloid peptide A␤ 1-42 and the ␣7 nicotinic acetylcholine receptor (␣7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of A␤ 1-42 to ␣7nAChR and ␣4␤2nAChR were determined using the subtypeselective nicotinic receptor ligands [3 H]methyllycaconitine and [3 H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. A␤ 1-42 bound to the ␣7nAChR with exceptionally high affinity, as indicated by K i values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the ␣7nAChR, the affinity of A␤ 1-42 for the ␣4␤2nAChR was ϳ5,000-fold lower, as indicated by corresponding K i values of 30 and 23 nM. The results of this study support the concept that an exceptionally high affinity interaction between A␤ 1-42 and ␣7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

“…While our current studies support A␤ 42 -evoked glutamate release is completely modulated through the ␣7nAChR, A␤ 42 can bind the ␣4␤2nAChR at 100-5000 times higher concentration than ␣7nAChR [10]. Furthermore, Mura and colleagues [8] reported A␤ had a dual effect on the ␣7 and ␣4␤2nAChR in the rat hippocampus.…”

“…Second, the ␣7nAChR-A␤ 42 complex may become internalized in both neurons and astrocytes, leading to plaque formation and eventual host cell lysis and plaque deposition [50]. Third, the ␣7nAChR-A␤ 42 may serve as the initial scaffold for A␤ 42 aggregation and eventual plaque accumulation [10] resulting in AD neuropathological progression [36] as previously mentioned. Taken together, these data suggest that A␤ 42 accumulation causes a functional blockade of the ␣7nAChR that impairs neuromodulation and potentially cognition, which may support why drugs targeting the cholinergic and glutamatergic systems in later stages of AD are largely unsuccessful.…”

“…A␤ 42 binds to the ␣7 nicotinic acetylcholine receptor (␣7nAChR) with picomolar affinity [10] and activation of this receptor is known to stimulate glutamate release [11]. Glutamate, the predominant excitatory neurotransmitter in the mammalian CNS, has a strong prevalence in neocortical and hippocampal pyramidal neurons and, therefore, plays a critical role in learning and memory [12].…”

Unconventional ligands and modulators of nicotinic receptors

“…For example, in biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either ␣7 nAChRs or APP, A␤1-42 can be coimmunoprecipitated with ␣7 nAChRs (Wang et al, 2000a). In addition to displacing binding of [ 3 H]-MLA from ␣7 nAChRs in cerebral cortical and hippocampal synaptosomes (Wang et al, 2000b), A␤1-42 at picomolar concentrations activates ␣7 nAChRs ectopically expressed in Xenopus oocytes (Dineley et al, 2002). At nanomolar concentrations, however, A␤1-42 blocks the activity of ␣7 nAChRs in rat hippocampal slices (Pettit et al, 2001) and in primary cultures of rat hippocampus and chick ciliary ganglion (Liu et al, 2001).…”

Rat neuronal nicotinic acetylcholine receptors containing α7 subunit: pharmacological properties of ligand binding and function

“…The α7 nAChRs have been implicated in a wide range of physiological functions, including neurotransmitter release [15,16] , activation of second messengers, apoptosis and neuroprotection [17,18] . More recent evidence indicates that α7 nAChRs may be directly involved in learning and memory [19,20] , pathology of Alzheimer's disease [21][22][23] , and inflammation [24] . The advance in our understanding of the biological properties and roles of α7* nAChRs has suggested new therapeutic strategies and drug candidates targeting α7 nAChRs for treatment of CNS disorders, including Alzheimer's disease [25,26] .…”