title: Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer's-like deficits in mice modeling the disease.
abstract: Rapamycin, an inhibitor of target-of-rapamycin, extends lifespan in mice, possibly by delaying aging. We recently showed that rapamycin halts the progression of Alzheimer's (AD)-like deficits, reduces amyloid-beta (Aβ) and induces autophagy in the human amyloid precursor protein (PDAPP) mouse model. To delineate the mechanisms by which chronic rapamycin delays AD we determined proteomic signatures in brains of control- and rapamycin-treated PDAPP mice. Proteins with reported chaperone-like activity were overrepresented among proteins up-regulated in rapamycin-fed PDAPP mice and the master regulator of the heat-shock response, heat-shock factor 1, was activated. This was accompanied by the up-regulation of classical chaperones/heat shock proteins (HSPs) in brains of rapamycin-fed PDAPP mice. The abundance of most HSP mRNAs except for alpha B-crystallin, however, was unchanged, and the cap-dependent translation inhibitor 4E-BP was active, suggesting that increased expression of HSPs and proteins with chaperone activity may result from preferential translation of pre-existing mRNAs as a consequence of inhibition of cap-dependent translation. The effects of rapamycin on the reduction of Aβ, up-regulation of chaperones, and amelioration of AD-like cognitive deficits were recapitulated by transgenic over-expression of heat-shock factor 1 in PDAPP mice. These results suggest that, in addition to inducing autophagy, rapamycin preserves proteostasis by increasing chaperones. We propose that the failure of proteostasis associated with aging may be a key event enabling AD, and that chronic inhibition of target-of-rapamycin may delay AD by maintaining proteostasis in brain. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12098.
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Anson
authors.initials: A
authors.lastname: Pierce
authors.forename: Natalia
authors.initials: N
authors.lastname: Podlutskaya
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Halloran
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Hussong
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Lin
authors.forename: Raquel
authors.initials: R
authors.lastname: Burbank
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hart
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus