Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice

Tatsuya Hoshino, Naoya Murao, Takushi Namba, Masaya Takehara, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, Takahide Matsushima, Toshiharu Suzuki, Tohru Mizushima

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Abstract

Amyloid-β peptide (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). A β is generated by proteolysis of β-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-β1, stimulate this phagocytosis. In contrast, cellular up regulation of HSP70 expression provides cytoprotection against Aβ. HSP70 activity in relation to inhibition of Aβ oligomerization and stimulation of Aβ phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression ofHSP70could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of Aβ, Aβ plaque deposition, and neuronal and synaptic loss than control mice. Immuno blotting experiments and direct measurement of β- and γ-secretase activity suggested that over expression of HSP70 does not affect the production Aβ. In contrast, HSP70 over expression did lead to up regulation of the expression of Aβ-degrading enzyme and TGF-β1 both in vivo and in vitro. These results suggest that over expression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.

Original languageEnglish
Pages (from-to)5225-5234
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number14
DOIs
Publication statusPublished - 2011 Apr 6
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Hoshino, T., Murao, N., Namba, T., Takehara, M., Adachi, H., Katsuno, M., Sobue, G., Matsushima, T., Suzuki, T., & Mizushima, T. (2011). Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice. Journal of Neuroscience, 31(14), 5225-5234. https://doi.org/10.1523/JNEUROSCI.5478-10.2011