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

Anson Pierce, Natalia Podlutskaya, Jonathan J. Halloran, Stacy A. Hussong, Pei Yi Lin, Raquel Burbank, Matthew J. Hart, Veronica Galvan

    Research output: Contribution to journalArticle

    46 Citations (Scopus)

    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. Chronic inhibition of TOR or overexpression of HSF1, the master regulator of the heat shock response reduce amyloid, upregulate chaperones, and improve cognitive function in mice modeling Alzheimer's disease (AD). We propose that a mechanism by which chronic inhibition of TOR alleviates cognitive deficits involves preventing a decline in proteostasis that critically enables pathogenic processes of AD in aged brains.

    Original languageEnglish (US)
    Pages (from-to)880-893
    Number of pages14
    JournalJournal of Neurochemistry
    Volume124
    Issue number6
    DOIs
    StatePublished - Mar 2013

    Fingerprint

    Sirolimus
    Shock
    Hot Temperature
    Alzheimer Disease
    Brain
    Heat-Shock Proteins
    Heat-Shock Response
    Up-Regulation
    Autophagy
    Amyloid
    alpha-Crystallin B Chain
    Aging of materials
    Inhibition (Psychology)
    Proteins
    Amyloid beta-Protein Precursor
    RNA Precursors
    Proteomics
    Cognition
    Messenger RNA

    Keywords

    • Alzheimer's disease
    • chaperones
    • heat shock factor 1
    • proteostasis
    • rapamycin
    • TOR

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

    Cite this

    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. / Pierce, Anson; Podlutskaya, Natalia; Halloran, Jonathan J.; Hussong, Stacy A.; Lin, Pei Yi; Burbank, Raquel; Hart, Matthew J.; Galvan, Veronica.

    In: Journal of Neurochemistry, Vol. 124, No. 6, 03.2013, p. 880-893.

    Research output: Contribution to journalArticle

    Pierce, Anson ; Podlutskaya, Natalia ; Halloran, Jonathan J. ; Hussong, Stacy A. ; Lin, Pei Yi ; Burbank, Raquel ; Hart, Matthew J. ; Galvan, Veronica. / 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. In: Journal of Neurochemistry. 2013 ; Vol. 124, No. 6. pp. 880-893.
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