Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease.
BACKGROUND
Abeta deposits represent a neuropathological hallmark of Alzheimer's disease (AD). Both soluble and insoluble Abeta species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Abeta production or accumulation remains a priority. NFkappaB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Abeta. We therefore explored whether the known NFkappaB inhibitor celastrol could represent a suitable compound for decreasing Abeta production and accumulation in vivo.


METHODS
The effect of celastrol on amyloid precursor protein (APP) processing, Abeta production and NFkappaB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Abeta accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol.


RESULTS
In vitro, celastrol dose dependently prevented NFkappaB activation and inhibited BACE-1 expression. Celastrol potently inhibited Abeta1-40 and Abeta1-42 production by reducing the beta-cleavage of APP, leading to decreased levels of APP-CTFbeta and APPsbeta. In vivo, celastrol appeared to reduce the levels of both soluble and insoluble Abeta1-38, Abeta1-40 and Abeta1-42. In addition, a reduction in Abeta plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol.


CONCLUSIONS
Overall our data suggest that celastrol is a potent Abeta lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFkappaB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.
Paris
Daniel
D
The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. dparis@rfdn.org
Ganey
Nowell J
NJ
Laporte
Vincent
V
Patel
Nikunj S
NS
Beaulieu-Abdelahad
David
D
Bachmeier
Corbin
C
March
Amelia
A
Ait-Ghezala
Ghania
G
Mullan
Michael J
MJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010703:Phorbol Esters / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection / Q000379:methods; D014315:Triterpenes / Q000737:chemistry / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002273:Carcinogens; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C508853:PSEN1 protein, human; D053978:Pentacyclic Triterpenes; D010703:Phorbol Esters; D053764:Presenilin-1; D014315:Triterpenes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C050414:celastrol