Abstract
Despite the ever-increasing number of patients with dementia worldwide, fundamental therapeutic approaches to this condition have not been established. Epidemiological studies suggest that intake of fermented dairy products prevents cognitive decline in the elderly. However, the active compounds responsible for the effect remain to be elucidated. The present study aims to elucidate the preventive effects of dairy products on Alzheimer's disease and to identify the responsible component. Here, in a mouse model of Alzheimer's disease (5xFAD), intake of a dairy product fermented with Penicillium candidum had preventive effects on the disease by reducing the accumulation of amyloid β (Aβ) and hippocampal inflammation (TNF-α and MIP-1α production), and enhancing hippocampal neurotrophic factors (BDNF and GDNF). A search for preventive substances in the fermented dairy product identified oleamide as a novel dual-active component that enhanced microglial Aβ phagocytosis and anti-inflammatory activity towards LPS stimulation in vitro and in vivo. During the fermentation, oleamide was synthesized from oleic acid, which is an abundant component of general dairy products owing to lipase enzymatic amidation. The present study has demonstrated the preventive effect of dairy products on Alzheimer's disease, which was previously reported only epidemiologically. Moreover, oleamide has been identified as an active component of dairy products that is considered to reduce Aβ accumulation via enhanced microglial phagocytosis, and to suppress microglial inflammation after Aβ deposition. Because fermented dairy products such as camembert cheese are easy to ingest safely as a daily meal, their consumption might represent a preventive strategy for dementia.
MeSH terms
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Alzheimer Disease / immunology
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Alzheimer Disease / metabolism
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Alzheimer Disease / prevention & control*
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Amyloid beta-Peptides / metabolism
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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Brain / drug effects
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Brain / immunology
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Brain / metabolism
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Cells, Cultured
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Cultured Milk Products / chemistry*
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Cultured Milk Products / microbiology
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Female
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Fermentation
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Humans
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Male
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Mice, Inbred C57BL
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Mice, Transgenic
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Microglia / drug effects
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Microglia / physiology*
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Oleic Acids / pharmacology*
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Oleic Acids / therapeutic use
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Penicillium / physiology
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Peptide Fragments / metabolism
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Phagocytosis / drug effects
Substances
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Amyloid beta-Peptides
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Anti-Inflammatory Agents
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Oleic Acids
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Peptide Fragments
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amyloid beta-protein (1-42)
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oleylamide
Grants and funding
The authors received no specific funding for this work. Kirin Company Ltd. and Koiwai Dairy Products Co., Ltd. provided support in the form of salaries for authors Y.A., T.K., A.Y. and S.S., but did not have any role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.]. Pls also update COI: [We declare the following interests. Yasuhisa Ano, Toshiko Kutsukake and Aruto Yoshida are employed by Kirin Company Ltd., and Shinya Sugiyama is employed by Koiwai Dairy Products Co., Ltd. Koiwai Dairy Foods Co., Ltd. is a subsidiary company of Kirin Company, Ltd., and all research was executed at Kirin Company, Ltd. using Kirin’s sources under a joint research agreement between Kirin and Koiwai. This does not alter our adherence to all of the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.