PMID- 28158298 OWN - NLM STAT- MEDLINE DCOM- 20170825 LR - 20190208 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 2 DP - 2017 TI - Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice. PG - e0171515 LID - 10.1371/journal.pone.0171515 [doi] LID - e0171515 AB - There is a growing interest in identifying natural food ingredients that may serve to prevent dementia such as that due to Alzheimer disease (AD). Peptides derived from food proteins have been demonstrated to have various physiological activities such as a hypotensive action. Recent findings have indicated possible associations of hypertension with AD progression, and suggest that angiotensin converting enzyme (ACE) inhibitors with potential to pass through the blood brain barrier (BBB) may reduce the risk of AD. In this study, we investigated the effect of milk peptide (CH-3) on cognitive function in AD model mice. CH-3 contains a tripeptide (methionine-lysine-proline, MKP) that has been found to have a strong ACE inhibitory effect and the potential to pass through the BBB. Adult male ddY mice were used in this study, and an animal model of AD was induced by intracerebroventricular (ICV) injection of Abeta1-42. CH-3 (250 mg/kg/day) or MKP (0.5 mg/kg/day) was orally administered every day starting 2 days before ICV injection. At 3 weeks after ICV injection, cognitive function was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and expression of inflammatory cytokines and NADPH oxidase subunits was measured by real-time quantitative RT-PCR. ICV injection of Abeta1-42 significantly impaired cognitive function compared with that in PBS-injected mice. Daily administration of CH-3 markedly attenuated this Abeta1-42-induced cognitive decline. Abeta1-42 injection significantly enhanced the expression of tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and p22phox in the mouse hippocampus compared with PBS injection, and showed a tendency to increase the expression of monocyte chemoattractant protein-1 (MCP-1), p47phox and gp91phox, whereas CH-3 treatment markedly reduced Abeta1-42-induced TNF-alpha, MCP-1, iNOS, p47phox and gp91phox expression. Finally, administration of MKP also attenuated Abeta1-42-induced cognitive impairment with an increase in cerebral blood flow. The present study demonstrated that repeated oral administration of CH-3 to AD model mice not only improved cognitive function but also suppressed the expression of inflammatory cytokines and production of oxidative stress, and suggests its therapeutic potential for preventing cognitive impairment in AD. FAU - Min, Li-Juan AU - Min LJ AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. FAU - Kobayashi, Yodai AU - Kobayashi Y AD - Morinaga Milk Industry Co., Ltd., Zama, Kanagawa, Japan. FAU - Mogi, Masaki AU - Mogi M AUID- ORCID: 0000-0002-0275-9198 AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. FAU - Tsukuda, Kana AU - Tsukuda K AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. FAU - Yamada, Akio AU - Yamada A AD - Morinaga Milk Industry Co., Ltd., Zama, Kanagawa, Japan. FAU - Yamauchi, Koji AU - Yamauchi K AD - Morinaga Milk Industry Co., Ltd., Zama, Kanagawa, Japan. FAU - Abe, Fumiaki AU - Abe F AD - Morinaga Milk Industry Co., Ltd., Zama, Kanagawa, Japan. FAU - Iwanami, Jun AU - Iwanami J AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. FAU - Xiao, Jin-Zhong AU - Xiao JZ AD - Morinaga Milk Industry Co., Ltd., Zama, Kanagawa, Japan. FAU - Horiuchi, Masatsugu AU - Horiuchi M AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan. LA - eng PT - Journal Article DEP - 20170203 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Amyloid beta-Peptides) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (CH-3 casein hydrolysate) RN - 0 (Caseins) RN - 0 (Neuroprotective Agents) RN - 0 (Oligopeptides) RN - 0 (Peptide Fragments) RN - 0 (Protein Hydrolysates) RN - 0 (amyloid beta-protein (1-42)) RN - 0 (methionyl-lysyl-proline) SB - IM MH - Alzheimer Disease/*drug therapy/pathology/physiopathology MH - Amyloid beta-Peptides/administration & dosage MH - Angiotensin-Converting Enzyme Inhibitors/*therapeutic use MH - Animals MH - Brain/drug effects/pathology MH - Caseins/chemistry/*therapeutic use MH - Cattle MH - Cognition/*drug effects MH - Disease Models, Animal MH - Inflammation/prevention & control MH - Male MH - Maze Learning/drug effects MH - Mice MH - Neuroprotective Agents/*therapeutic use MH - Oligopeptides/chemistry/*therapeutic use MH - Peptide Fragments/administration & dosage MH - Protein Hydrolysates/chemistry/*therapeutic use MH - Rats MH - Rats, Inbred SHR PMC - PMC5291428 COIS- Yodai Kobayashi, Akio Yamada, Koji Yamauchi, Fumiaki Abe and Jin-Zhong Xiao are employed by Morinaga Milk Industry Co., Ltd. This does not alter the authors' adherence to all of the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. EDAT- 2017/02/06 06:00 MHDA- 2017/08/26 06:00 PMCR- 2017/02/03 CRDT- 2017/02/04 06:00 PHST- 2016/07/11 00:00 [received] PHST- 2017/01/03 00:00 [accepted] PHST- 2017/02/04 06:00 [entrez] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/08/26 06:00 [medline] PHST- 2017/02/03 00:00 [pmc-release] AID - PONE-D-16-27540 [pii] AID - 10.1371/journal.pone.0171515 [doi] PST - epublish SO - PLoS One. 2017 Feb 3;12(2):e0171515. doi: 10.1371/journal.pone.0171515. eCollection 2017.