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Suppression of Alzheimer's Disease-Related Phenotypes by Geranylgeranylacetone in Mice

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Title: Suppression of Alzheimer's Disease-Related Phenotypes by Geranylgeranylacetone in Mice
Authors: Hoshino, Tatsuya Browse this author
Suzuki, Koichiro Browse this author
Matsushima, Takahide Browse this author
Yamakawa, Naoki Browse this author
Suzuki, Toshiharu Browse this author →KAKEN DB
Mizushima, Tohru Browse this author →KAKEN DB
Issue Date: 1-Oct-2013
Publisher: Public library science
Journal Title: Plos one
Volume: 8
Issue: 10
Start Page: e76306
Publisher DOI: 10.1371/journal.pone.0076306
PMID: 24098472
Abstract: Amyloid-beta peptide (A beta) plays an important role in the pathogenesis of Alzheimer's disease (AD). A beta is generated by the secretase-mediated proteolysis of beta-amyloid precursor protein (APP), and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF)-beta 1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of A beta, A beta plaque deposition and synaptic loss. The treatment also up-regulated the expression of an A beta-degrading enzyme and TGF-beta 1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when A beta was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 利治

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