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

Nigel H. Greig, Tadanobu Utsuki, Donald K. Ingram, Yue Wang, Giancarlo Pepeu, Carla Scali, Qian Sheng Yu, Jacek Mamczarz, Harold W. Holloway, Tony Giordano, Demao Chen, Katsutoshi Furukawa, Kumar Sambamurti, Arnold Brossi, Debomoy Lahiri

Research output: Contribution to journalArticle

443 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)17213-17218
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number47
DOIs
StatePublished - Nov 22 2005

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Butyrylcholinesterase
Amyloid
Acetylcholine
Rodentia
Learning
Peptides
Brain
Acetylcholinesterase
Alzheimer Disease
Long-Term Potentiation
Amyloid beta-Protein Precursor
Mutant Proteins
Neuroblastoma
Cognition
Cholinergic Agents
Transgenic Mice
Neurotransmitter Agents
Cell Survival
Central Nervous System
Inhibition (Psychology)

Keywords

  • Anticholinesterase
  • Dementia
  • Long-term potentiation
  • Memory
  • Neurodegeneration

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent. / Greig, Nigel H.; Utsuki, Tadanobu; Ingram, Donald K.; Wang, Yue; Pepeu, Giancarlo; Scali, Carla; Yu, Qian Sheng; Mamczarz, Jacek; Holloway, Harold W.; Giordano, Tony; Chen, Demao; Furukawa, Katsutoshi; Sambamurti, Kumar; Brossi, Arnold; Lahiri, Debomoy.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 47, 22.11.2005, p. 17213-17218.

Research output: Contribution to journalArticle

Greig, NH, Utsuki, T, Ingram, DK, Wang, Y, Pepeu, G, Scali, C, Yu, QS, Mamczarz, J, Holloway, HW, Giordano, T, Chen, D, Furukawa, K, Sambamurti, K, Brossi, A & Lahiri, D 2005, 'Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 47, pp. 17213-17218. https://doi.org/10.1073/pnas.0508575102
Greig, Nigel H. ; Utsuki, Tadanobu ; Ingram, Donald K. ; Wang, Yue ; Pepeu, Giancarlo ; Scali, Carla ; Yu, Qian Sheng ; Mamczarz, Jacek ; Holloway, Harold W. ; Giordano, Tony ; Chen, Demao ; Furukawa, Katsutoshi ; Sambamurti, Kumar ; Brossi, Arnold ; Lahiri, Debomoy. / Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 47. pp. 17213-17218.
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