Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

被引:656
作者
Greig, NH [1 ]
Utsuki, T
Ingram, DK
Wang, Y
Pepeu, G
Scali, C
Yu, QS
Mamczarz, J
Holloway, HW
Giordano, T
Chen, DM
Furukawa, K
Sambamurti, K
Brossi, A
Lahiri, DK
机构
[1] NIA, Neurosci Lab, Baltimore, MD 21224 USA
[2] NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA
[3] Univ Florence, Dept Pharmacol, I-50139 Florence, Italy
[4] Louisiana State Univ, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA
[5] Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA
[6] Univ N Carolina, Chapel Hill, NC 27599 USA
[7] Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA
关键词
anticholinesterase; long-term potentiation; dementia; memory; neurodegeneration;
D O I
10.1073/pnas.0508575102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that over-expressed human mutant amyloid precursor protein also resulted in lower beta-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.
引用
收藏
页码:17213 / 17218
页数:6
相关论文
共 50 条
[1]   Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice [J].
Anagnostaras, SG ;
Murphy, GG ;
Hamilton, SE ;
Mitchell, SL ;
Rahnama, NP ;
Nathanson, NM ;
Silva, AJ .
NATURE NEUROSCIENCE, 2003, 6 (01) :51-58
[2]   CHANGES IN ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE IN ALZHEIMERS-DISEASE RESEMBLE EMBRYONIC-DEVELOPMENT - A STUDY OF MOLECULAR-FORMS [J].
ARENDT, T ;
BRUCKNER, MK ;
LANGE, M ;
BIGL, V .
NEUROCHEMISTRY INTERNATIONAL, 1992, 21 (03) :381-396
[3]  
Ballard Clive G., 2005, Current Alzheimer Research, V2, P307
[4]   Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins [J].
Borchelt, DR ;
Ratovitski, T ;
vanLare, J ;
Lee, MK ;
Gonzales, V ;
Jenkins, NA ;
Copeland, NG ;
Price, DL ;
Sisodia, SS .
NEURON, 1997, 19 (04) :939-945
[5]   Endocannabinoids facilitate the induction of LTP in the hippocampus [J].
Carlson, G ;
Wang, Y ;
Alger, BE .
NATURE NEUROSCIENCE, 2002, 5 (08) :723-724
[6]   Cholinergic plasticity in the hippocarnpus [J].
Colgin, LL ;
Kubota, D ;
Lynch, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2872-2877
[7]   DEMENTIA - THE NEUROCHEMICAL BASIS OF PUTATIVE TRANSMITTER ORIENTATED THERAPY [J].
COURT, JA ;
PERRY, EK .
PHARMACOLOGY & THERAPEUTICS, 1991, 52 (03) :423-443
[8]   Neurobiology of butyrylcholinesterase [J].
Darvesh, S ;
Hopkins, DA ;
Geula, C .
NATURE REVIEWS NEUROSCIENCE, 2003, 4 (02) :131-138
[9]  
Darvesh S, 1998, J COMP NEUROL, V393, P374
[10]   A NEW AND RAPID COLORIMETRIC DETERMINATION OF ACETYLCHOLINESTERASE ACTIVITY [J].
ELLMAN, GL ;
COURTNEY, KD ;
ANDRES, V ;
FEATHERSTONE, RM .
BIOCHEMICAL PHARMACOLOGY, 1961, 7 (02) :88-&