title: An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice.
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.
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Gao
authors.affiliation: Department of Immunology, China Medical University, Shenyang, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nabeka
authors.affiliation: Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shimokawa
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Immunology, China Medical University, Shenyang, China.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Cao
authors.affiliation: Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsuda
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011897:Random Allocation; D049231:Saposins / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D010446:Peptide Fragments; D010455:Peptides; C483344:Psap protein, mouse; D049231:Saposins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D002795:Choline O-Acetyltransferase; D010751:Phosphopyruvate Hydratase; D000109:Acetylcholine
keywords: Akt/GSK-3α/β; Alzheimer’s disease; Aβ1–42 peptide; apoptosis; neurogenesis; prosaposin