Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid ␤-amyloid peptide (A␤ 1-42 ) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that A␤ 1-42 and a neuronal pentameric cation channel, the ␣7 nicotinic acetylcholine receptor (␣7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either ␣7nAChR or amyloid precursor protein as the starting material, A␤ 1-42 and ␣7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the ␣7nAChR⅐A␤ 1-42 complex can be efficiently suppressed by A␤ 12-28 , implying that this A␤ sequence region contains the binding epitope. Receptor binding experiments show that A␤ 1-42 and ␣7nAChR bind with high affinity, and this interaction can be inhibited by ␣7nAChR ligands. Human neuroblastoma cells overexpressing ␣7nAChR are readily killed by A␤ 1-42 , whereas ␣7nAChR agonists such as nicotine and epibatidine offered protection. Because A␤ 1-42 inhibits ␣7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of ␣7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the ␣7nAChR and A␤ 1-42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.Evidence obtained from familial Alzheimer's disease (AD) 1 patients (1-3) and transgenic animals (4 -7) overexpressing amyloid precursor protein (APP) indicates that A␤ 1-42 is a causal factor of neuritic plaque formation and neurodegeneration in AD. A␤ peptides are known to bind specifically to the scavenger receptors expressed in microglia and macrophages (8, 9) and the ubiquitous receptor for advanced glycation end products (RAGE) (10, 11). A␤ binding to scavenger receptors may induce cell death by generating free radicals (12, 13), whereas binding to RAGE may promote A␤ clearance (10, 11). However, the respective receptor function and distribution pattern for scavenger receptors and RAGE cannot fully explain the A␤ 1-42 -induced pathophysiology observed in AD such as cognitive and memory impairment, in which cholinergic neurons are involved. This suggests that additional physiologically relevant neuronal receptors for A␤ 1-42 may exist.The ␣7 nicotinic acetylcholine receptor (␣7nAChR) is highly expressed in the basal forebrain cholinergic neurons that project to the hippocampus and cortex of normal and AD brains (14, 15), correlating well with brain areas that exhibit neuritic plaques in AD. More importantly, the ␣7nAChR modulates calcium homeostasis and release of the neurotransmitter acetylcholine, two important parameters involved in cognition and memory. We thus investigated the molecular and bioche...

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.

No abstract

No abstract

The production and aggregation of cerebral amyloid-␤ (A␤) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both A␤ and the amyloid precursor protein (APP). The inverse correlation of A␤ levels with NgR levels within the brain may reflect regulation of A␤ production and/or A␤ clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated A␤ clearance in APPswe/PSEN-1⌬E9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of A␤ associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain A␤ plaque load while increasing the relative levels of serum A␤. These changes in A␤ are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central A␤ residues provides an effective therapeutic approach for AD.