Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer's disease

被引：29

作者：

Ho S.W. ^{[1
]}

Tsui Y.T.C. ^{[2
]}

Wong T.T. ^{[2
]}

Cheung S.K.K. ^{[3
]}

Goggins W.B. ^{[4
]}

Yi L.M. ^{[5
]}

Cheng K.K. ^{[5
]}

Baum L. ^{[5
]}

机构：

[1] Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong

[2] School of Biomedical Sciences (Pharmacology), The University of Nottingham, Nottingham

[3] Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong

[4] School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong

[5] School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong

来源：

Translational Neurodegeneration | / 2卷 / 1期

关键词：

Dementia; Mouse; Plaques; Tangles;

D O I：

10.1186/2047-9158-2-24

中图分类号：

学科分类号：

摘要：

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. © 2013 Ho et al.; licensee BioMed Central Ltd.

引用

共 64 条

[1]

Hardy J., The amyloid hypothesis for Alzheimer's disease: a critical reappraisal, J Neurochem, 110, pp. 1129-1134, (2009)

[2]

Hardy J., Selkoe D.J., The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science, 297, pp. 353-356, (2002)

[3]

Newell K.L., Hyman B.T., Growdon J.H., Hedley-Whyte E.T., Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease, J Neuropathol Exp Neurol, 58, pp. 1147-1155, (1999)

[4]

Ubhi K., Masliah E., Alzheimer's disease: recent advances and future perspectives, J Alzheimers Dis, 33, SUPPL 1, (2013)

[5]

Cheng B., Gong H., Xiao H., Petersen R.B., Zheng L., Huang K., Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases, Biochim Biophys Acta, 2013, pp. 4860-4871, (1830)

[6]

Yam G.H., Wang K., Jhanji V., Choy K.W., Baum L., Pang C.P., In vitro amyloid aggregate forming ability of TGFBI mutants that cause corneal dystrophies, Invest Ophthalmol Vis Sci, 53, pp. 5890-5898, (2012)

[7]

Zhao H.L., Sui Y., Guan J., He L., Gu X.M., Wong H.K., Baum L., Lai F.M., Tong P.C., Chan J.C., Amyloid oligomers in diabetic and nondiabetic human pancreas, Transl Res, 153, pp. 24-32, (2009)

[8]

Lewis J., McGowan E., Rockwood J., Melrose H., Nacharaju P., Van S.M., Gwinn-Hardy K., Paul M.M., Baker M., Yu X., Duff K., Hardy J., Corral A., Lin W.L., Yen S.H., Dickson D.W., Davies P., Hutton M., Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein, Nat Genet, 25, pp. 402-405, (2000)

[9]

Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., Yang F., Cole G., Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice, Science, 274, pp. 99-102, (1996)

[10]

Gotz J., Deters N., Doldissen A., Bokhari L., Ke Y., Wiesner A., Schonrock N., Ittner L.M., A decade of tau transgenic animal models and beyond, Brain Pathol, 17, pp. 91-103, (2007)

← 1 2 3 4 5 6 7 →