Affiliations: [a]
College of Life and Health Sciences, Northeastern University, Shenyang, China
| [b]
Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| [c]
Department of Immunology, China Medical University, Shenyang, China
Correspondence:
[*]
Correspondence to: Hui-ling Gao, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China. Tel./Fax: +86 24 83656108; E-mail: ghllch@hotmail.com and Hiroaki Nabeka, Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan. Tel.: +81 89 960 5231; Fax: +81 89 960 5233; E-mail: nabeka@m.ehime-u.ac.jp.
Abstract: The pathological hallmarks of Alzheimer’s disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1–42 peptide. Seven days after Aβ1–42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1–42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1–42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1–42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1–42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.
