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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...

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH P ) is a highly selective and potent agonist of the W W-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis-and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis-and trans-configurations with morphine and selective W Wpeptide ligands PL-017 and D-TIPP, as well as the N N-selective peptide ligands TIPP (N N-antagonist, W W-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain W W-and N Nselectivity based on the presence of spatially distinct selectivity pockets among these ligands.z 1998 Federation of European Biochemical Societies.