Dissociating beta-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.
Alzheimer's disease (AD) is characterized by synaptic dysfunction and cardinal neuropathological features including amyloid plaques and neurofibrillary tangles. Soluble amyloid-beta (Abeta) can suppress synaptic activities by interacting with alpha7 nicotinic acetylcholine receptors (alpha7nAChRs). Here, we show that alpha7nAChR and NMDA glutamatergic receptor (NMDAR) activities are severely compromised in synaptosomes prepared from AD and Abeta(1-42) (Abeta42)-exposed control frontal cortex slices from postmortem tissue. Whereas Abeta(12-28) prevents Abeta42 from binding to alpha7nAChRs, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a novel alpha7nAChR partial agonist, facilitates release of Abeta42 from Abeta42-alpha7nAChR and -Abeta42 complexes. S 24795 interacts with alpha7nAChR and Abeta(15-20) region of the Abeta42 to enable partial recovery of the alpha7nAChR and NMDAR channel function. These findings suggest that the Abeta-alpha7nAChR 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 Abeta from alpha7nAChRs.
Wang
Hoau-Yan
HY
Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, New York 10031, USA. hywang@sci.ccny.cuny.edu
Stucky
Andres
A
Liu
JingJing
J
Shen
Changpeng
C
Trocme-Thibierge
Caryn
C
Morain
Philippe
P
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D005260:Female; D006801:Humans; D008297:Male; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D011726:Pyridinium Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C524163:S 24795; D064569:alpha7 Nicotinic Acetylcholine Receptor