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The Journal of Neuroscience, September 2, 2009, 29(35):10961-10973; doi:10.1523/JNEUROSCI.6088-08.2009

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Neurobiology of Disease
Dissociating β-Amyloid from {alpha}7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes {alpha}7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain

Hoau-Yan Wang,1 Andres Stucky,1 JingJing Liu,1 Changpeng Shen,1 Caryn Trocme-Thibierge,2 and Philippe Morain2 {dagger}

1Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, New York 10031, and 2Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France

Correspondence should be addressed to Hoau-Yan Wang, Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, City University of New York Medical School, H-210F, Harris Hall, 160 Convent Avenue, New York, NY 10031. Email: hywang{at}sci.ccny.cuny.edu

Alzheimer's disease (AD) is characterized by synaptic dysfunction and cardinal neuropathological features including amyloid plaques and neurofibrillary tangles. Soluble amyloid-β (Aβ) can suppress synaptic activities by interacting with {alpha}7 nicotinic acetylcholine receptors ({alpha}7nAChRs). Here, we show that {alpha}7nAChR and NMDA glutamatergic receptor (NMDAR) activities are severely compromised in synaptosomes prepared from AD and Aβ1-42 (Aβ42)-exposed control frontal cortex slices from postmortem tissue. Whereas Aβ12-28 prevents Aβ42 from binding to {alpha}7nAChRs, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a novel {alpha}7nAChR partial agonist, facilitates release of Aβ42 from Aβ42–{alpha}7nAChR and –Aβ42 complexes. S 24795 interacts with {alpha}7nAChR and Aβ15-20 region of the Aβ42 to enable partial recovery of the {alpha}7nAChR and NMDAR channel function. These findings suggest that the Aβ–{alpha}7nAChR interaction may be an upstream pathogenic event in AD and demonstrate that some recovery of neuronal channel activities may be achieved in AD brains by removing Aβ from {alpha}7nAChRs.

Received Dec. 22, 2008; revised July 22, 2009; accepted July 23, 2009.

Correspondence should be addressed to Hoau-Yan Wang, Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, City University of New York Medical School, H-210F, Harris Hall, 160 Convent Avenue, New York, NY 10031. Email: hywang{at}sci.ccny.cuny.edu






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