title: Neuropep-1 ameliorates learning and memory deficits in an Alzheimer's disease mouse model, increases brain-derived neurotrophic factor expression in the brain, and causes reduction of amyloid beta plaques.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library. Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aβ1-42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Min-Kyoo
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Hong-Gi
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Woo-Ram
authors.initials: WR
authors.lastname: Jung
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Dong-Ik
authors.initials: DI
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea. Electronic address: kimkl@skku.ac.kr.
authors.forename: Kil-Lyong
authors.initials: KL
authors.lastname: Kim
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000009:adverse effects; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000009:adverse effects; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000009:adverse effects; D058225:Plaque, Amyloid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; C000592076:Neuropep-1; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D015655:1-Methyl-4-phenylpyridinium
keywords: Alzheimer's disease; Amyloid beta; Brain-derived Neurotrophic Factor; Cognition; Peptide