Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice

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.

Melatonin ameliorates Aβ1-42-induced Alzheimer's cognitive deficits in mouse model

“…The establishment of AD model was conducted as protocol . The location of brain was verified in advance before the injection of Aβ 1‐42 : 2 mm posterior to bregma, 1.5 mm next to biparietal suture and 1 mm under skull.…”

“…The establishment of AD model was conducted as protocol. [26] The location of brain was verified in advance before the injection of Ab 1-42 : 2 mm posterior to bregma, 1.5 mm next to biparietal suture and 1 mm under skull. Holes were drilled in the skull, and 410 pm Ab 1-42 (5 ll) was injected into the hole in 2 min and the syringe was removed 2 min after injection.…”

Mechanisms of Neuroprotective Effects of Peptides Derived from Natural Materials and Their Production and Assessment

“…Min et al. () demonstrated that administration of milk peptide to AD model mice improved memory and suppressed the expression of inflammatory cytokines such as TNF‐α, marine collagen peptide (MCP)‐1, iNOS, p47 phox , and gp97 phox (Min et al., ). The 11 peptides obtained from porcine cerebral hydrolysate caused remarkable improvement of spatial memory and escape latency, in addition to significantly reducing the production of ROS and MDA compared to Pb 2± ‐exposed mice (Zou et al., ).…”

“…Moreover, combinations of two or more enzymes may stimulate a higher degree of hydrolysis. Peptides with neuroprotective effects have been obtained from food proteins, including plant proteins (Chen et al., ; Jin et al., ; Li et al., ), meat proteins (Kim et al., ; Min et al., ; Wang et al., ), and marine proteins (Chai et al., ; Lin et al., ; Zhao et al., ). Li et al.…”

Emerging roles of bioactive peptides on brain health promotion

“…Neurotrophic peptides derived from bovine milk and its fermented products have received increasing attention. The administration of bovine casein hydrolysate prevented cognitive decline in AD model mice, with a reduction of inflammation and oxidative stress (Min et al, 2017). Furthermore, MKP, a tripeptide with greater blood-brain barrier (BBB) penetration, was one of the primary players in the prevention of cognitive impairment (Table 1).…”