Open AccessPNU282987 inhibits amyloid‑β aggregation by upregulating astrocytic endogenous αB‑crystallin and HSP‑70 via regulation of the α7AChR, PI3K/Akt/HSF‑1 signaling axis
Author(s) -
Zhen Ren,
Zhihui Dong,
Peng Xie,
Ju Lv,
Yumei Hu,
ZhiZhong Guan,
Chunlin Zhang,
Wenfeng Yu
Publication year - 2020
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2020.11132
Subject(s) - methyllycaconitine , ly294002 , neuroprotection , protein kinase b , downregulation and upregulation , pi3k/akt/mtor pathway , microbiology and biotechnology , chemistry , heat shock protein , gene knockdown , astrogliosis , biology , signal transduction , pharmacology , receptor , nicotinic acetylcholine receptor , biochemistry , apoptosis , nicotinic agonist , endocrinology , gene , central nervous system
Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder. Abnormal aggregation of the neurotoxic amyloid‑β (Aβ) peptide is an early event in AD. The activation of astrocytic α7 nicotinic acetylcholine receptor (α7 nAChR) can inhibit Aβ aggregation; thus, the molecular mechanism between α7 nAChR activation and Aβ aggregation warrants further investigation. In the present study, Aβ oligomer levels were assessed in astrocytic cell lysates after treatment with PNU282987 (a potent agonist of α7 nAChRs) or co‑treatment with LY294002, a p‑Akt inhibitor. The levels of heat shock factor‑1 (HSF‑1), heat shock protein 70 (HSP‑70), and αB‑crystallin (Cryab) in astrocytes treated with PNU282987 at various time‑points or co‑treated with methyllycaconitine (MLA), a selective α7 nAChR antagonist, as well as co‑incubated with LY294002 were determined by western blotting. HSP‑70 and Cryab levels were determined after HSF‑1 knockdown (KD) in astrocytes. PNU282987 markedly inhibited Aβ aggregation and upregulated HSF‑1, Cryab, and HSP‑70 in primary astrocytes, while the PNU282987‑mediated neuroprotective effect was reversed by pre‑treatment with MLA or LY294002. Moreover, the HSF‑1 KD in astrocytes effectively decreased Cryab, but not HSP‑70 expression. HSF‑1 is necessary for the upregulation of Cryab expression, but not for that of HSP‑70. HSF‑1 and HSP‑70 have a neuroprotective effect. Furthermore, the neuroprotective effect of PNU282987 against Aβ aggregation was mediated by the canonical PI3K/Akt signaling pathway activation.