Amyloid-β
peptide (Aβ) plays an important role in the pathogenesis of
Alzheimer's disease (AD). Aβ is generated by the
secretase-mediated proteolysis of β-
amyloid precursor
protein (APP), and cleared by
enzyme-mediated degradation and phagocytosis.
Transforming growth factor (TGF)-β1 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 Aβ, Aβ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an Aβ-degrading
enzyme and TGF-β1 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 Aβ 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.