title: Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer's disease.
abstract: Alzheimer's disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation.
authors.forename: Shuk Wai
authors.initials: SW
authors.lastname: Ho
authors.forename: Yuk Tung Chanel
authors.initials: YT
authors.lastname: Tsui
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Wong
authors.forename: Stanley Kwok-Kuen
authors.initials: SK
authors.lastname: Cheung
authors.forename: William B
authors.initials: WB
authors.lastname: Goggins
authors.forename: Lau Ming
authors.initials: LM
authors.lastname: Yi
authors.forename: Kwok Kin
authors.initials: KK
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China. lwbaum@cuhk.edu.hk.
authors.forename: Larry
authors.initials: L
authors.lastname: Baum