Suppression of Alzheimer's disease-related phenotypes by the heat shock protein 70 inducer, geranylgeranylacetone, in APP/PS1 transgenic mice via the ERK/p38 MAPK signaling pathway.

Abstract

HSP70 overexpression has a remedying effect in neurodegenerative diseases. In Alzheimer's disease (AD), the suppressive effects of HSP70 overexpression on AD-related phenotypes and the underlying mechanisms are unknown. In the current study, the effect of geranylgeranylacetone (GGA), a non-toxic inducer of heat shock protein (HSP)-70 expression, on cognitive function and other pathological phenotypes were evaluated in APP/PS1 mice. It was observed that all doses of orally administered GGA (200, 400, and 800 mg/kg/day) improved cognitive deficit (P<0.05) and lowered the levels of amyloid-β (Aβ) peptide (P<0.05) in APP/PS1 mice. GGA treatment also increased the levels of low density lipoprotein receptor-related protein 1 (LRP-1) (P<0.05), while the levels of p-glycoprotein and receptor for advanced glycation end products were unaltered. Significant decreases in the levels of inflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β and cyclooxygenase-2, were also observed in the GGA-treated mice (P<0.05). Subsequent treatment with the HSP70 inhibitor quercetin caused significant decreases in the levels of phosphorylated (p)-p38 mitogen-activated protein kinase (p38 MAPK) and p-extracellular signal-regulated protein kinases (ERK; P<0.05), indicating that ERK/p38 MAPK signaling in AD-related phenotypes may be suppressed by oral administration of GGA. Finally, in APP/PS1 mice treated with GGA+SB-203580 (p38 inhibitor) and GGA+PD98059 (ERK inhibitor), it was observed that orally administered GGA led to the activation of ERK/p38 MAPK signaling (P<0.05) and increased LRP-1 expression (P<0.05), which subsequently aided the clearance of Aβ40 and Aβ42 (P<0.05) and alleviated AD-related phenotypes. These results indicate that oral administration of GGA in APP/PS1 mice alleviates AD-related phenotypes by regulation of the ERK/p38 MAPK signaling pathway. Thus, GGA may be a potential therapeutic for the treatment of AD.