TY - JOUR
T1 - Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent
AU - Greig, Nigel H.
AU - Utsuki, Tadanobu
AU - Ingram, Donald K.
AU - Wang, Yue
AU - Pepeu, Giancarlo
AU - Scali, Carla
AU - Yu, Qian Sheng
AU - Mamczarz, Jacek
AU - Holloway, Harold W.
AU - Giordano, Tony
AU - Chen, Demao
AU - Furukawa, Katsutoshi
AU - Sambamurti, Kumar
AU - Brossi, Arnold
AU - Lahiri, Debomoy K.
PY - 2005/11/22
Y1 - 2005/11/22
N2 - Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular β-amyloid precursor protein, and secreted β-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower β-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
AB - Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular β-amyloid precursor protein, and secreted β-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower β-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
KW - Anticholinesterase
KW - Dementia
KW - Long-term potentiation
KW - Memory
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=28044437122&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28044437122&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508575102
DO - 10.1073/pnas.0508575102
M3 - Article
C2 - 16275899
AN - SCOPUS:28044437122
VL - 102
SP - 17213
EP - 17218
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
ER -