Abstract

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 Aβ1–42. 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 Aβ1–42 significantly impaired cognitive function compared with that in PBS-injected mice. Daily administration of CH-3 markedly attenuated this Aβ1-42-induced cognitive decline. Aβ1–42 injection significantly enhanced the expression of tumor necrosis factor-α (TNF-α), 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 Aβ1-42-induced TNF-α, MCP-1, iNOS, p47phox and gp91phox expression. Finally, administration of MKP also attenuated Aβ1-42-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.

Highlights

  • Alzheimer disease (AD), an irreversible progressive neurodegenerative disorder, is one of the most prevalent neurodegenerative diseases in aging societies

  • Time spent in the target quadrant including the former platform position was impaired in Aβ1-42-injected mice compared with control mice; Aβ1-42-injected mice with CH-3 treatment exhibited similar ability to recognize the platform compared with PBS-injected mice (Fig 1B)

  • To investigate the possible involvement of inflammation and oxidative stress in the improvement of Aβ 1-42-induced cognitive decline by CH-3, the mouse hippocampus was obtained after behavioral testing, and the expression of inflammatory cytokines and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits was assessed by real-time RT-PCR

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Summary

Introduction

Alzheimer disease (AD), an irreversible progressive neurodegenerative disorder, is one of the most prevalent neurodegenerative diseases in aging societies. It is associated with memory loss, and its typical symptoms are memory impairment and cognitive decline. It is becoming an increasing burden on patients and their families. In the brain of AD patients, Aβ deposition is a crucial pathological event [1]. Aβ deposition in the brain has been suggested to cause oxidative damage and neuroinflammation, which are closely associated with progression of AD [2,3,4]. There is growing interest in identifying possible natural food ingredients that can prevent AD onset and progression

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