Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity.

Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Research Abstract Details 

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Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Abstract Text:

Hongjun Fu,Wenming Li,Jialie Luo,Nelson T K Lee,Mingtao Li,Karl W K Tsim,Yuanping Pang,Moussa B H Youdim,Yifan Han,Hongjun Fu,Wenming Li,Jialie Luo,Nelson T K Lee,Mingtao Li,Karl W K Tsim,Yuanping Pang,Moussa B H Youdim,Yifan Han,

The regulation of alpha-, beta-, (BACE-1), and gamma-secretase activities to alter beta-amyloid (Abeta) generation is considered to be one of the most promising disease-modifying therapeutics for Alzheimer's disease. In this study, the effect and mechanisms of bis(7)-tacrine (a promising anti-Alzheimer's dimer) on Abeta generation were investigated. Bis(7)-tacrine (0.1-3muM) substantially reduced the amounts of both secreted and intracellular Abeta in Neuro2a APPswe cells without altering the expression of APP. sAPPalpha and CTFalpha increased, while sAPPbeta and CTFbeta decreased significantly in Neuro2a APPswe cells following the treatment with bis(7)-tacrine, indicating that bis(7)-tacrine might activate alpha-secretase and/or inhibit BACE-1 activity. Furthermore, bis(7)-tacrine concentration-dependently inhibited BACE-1 activity in cultured cells, and also in recombinant human BACE-1 in a non-competitive manner with an IC(50) of 7.5muM, but did not directly affect activities of BACE-2, Cathepsin D, alpha- or gamma-secretase. Taken together, our results not only suggest that bis(7)-tacrine may reduce the biosynthesis of Abeta mainly by directly inhibiting BACE-1 activity, but also provide new insights into the rational design of novel anti-Alzheimer's dimers that might have disease-modifying properties.

Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Publishing Authors By Initials

H Fu,W Li,J Luo,NT Lee,M Li,KW Tsim,Y Pang,MB Youdim,Y Han,H Fu,W Li,J Luo,NT Lee,M Li,KW Tsim,Y Pang,MB Youdim,Y Han,

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Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biochemical and biophysical research communication

VOLUME: 366

Page Numbers: 631-6

Journal Abbreviation: Biochem. Biophys. Res. Commun.

ISSN: 1090-2104

DAY: 26

MONTH: 11

YEAR: 2007

Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Information

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LANGUAGE: eng

NlmUniqueID: 372516

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Grant and Affiliation Information for Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity.

AFFILIATION: Department of Biochemistry, The Hong Kong University of Science and Technology, Hong Kong, China.

Country: United States

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MEDLINETA: Biochem Biophys Res Commun

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