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

Sun,Yuan; Zhang,Jiang‑Rong; Chen,Shuyan

doi:10.3892/etm.2017.5253

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

Authors:
- Yuan Sun
- Jiang‑Rong Zhang
- Shuyan Chen
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Affiliations: Department of Geratology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
Published online on: October 3, 2017 https://doi.org/10.3892/etm.2017.5253
Pages: 5267-5274
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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