Abstract
Altered cholesterol metabolism is believed to play a causal role in major pathophysiological changes in neurodegeneration. Several studies have demonstrated that the absence of apolipoprotein E (ApoE), a predominant apolipoprotein in the brain, leads to an increased susceptibility to neurodegeneration. Previously, we observed that genistein, a soy isoflavone, significantly alleviated apoptosis and tau hyperphosphorylation in SH-SY5Y cells. Therefore, we investigated the neuroprotective effects of dietary genistein supplementation (0.5 g/kg diet) in the cortex and hippocampus of wild-type C57BL/6 (WT) and ApoE knockout (ApoE-/-) mice fed a high-fat diet (HFD) for 24 weeks. Genistein supplementation alleviated neuroinflammation and peripheral and brain insulin resistance. Reductions in oxidative and endoplasmic reticulum stress were also observed in ApoE-/- mice fed a genistein-supplemented diet. Beta-secretase 1 and presenilin 1 mRNA levels and beta-amyloid peptide (Aβ) protein levels were reduced in response to genistein supplementation in ApoE-/- mice but not in WT mice. Although the absence of ApoE did not increase tau hyperphosphorylation, genistein supplementation reduced tau hyperphosphorylation in both WT and ApoE-/- mice. Consistent with this result, we also observed that genistein alleviated activity of c-Jun N-terminal kinase and glycogen synthase kinase 3β, which are involved in tau hyperphosphorylation. Taken together, these results demonstrate that genistein alleviated neuroinflammation, Aβ deposition, and hyperphosphorylation in ApoE-/- mice fed an HFD.
Keywords:
ApoE−/− mice; brain; genistein; neurodegeneration; neuroinflammation.
MeSH terms
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Alzheimer Disease / etiology
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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 Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Antioxidants / adverse effects
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Antioxidants / therapeutic use
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Cerebral Cortex / enzymology
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Cerebral Cortex / immunology
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Cerebral Cortex / metabolism*
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Diet, High-Fat / adverse effects
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Dietary Supplements*
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Endoplasmic Reticulum Stress
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Gene Expression Regulation
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Genistein / adverse effects
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Genistein / therapeutic use*
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Hippocampus / enzymology
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Hippocampus / immunology
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Hippocampus / metabolism*
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Male
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / enzymology
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Neurons / immunology
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Neurons / metabolism*
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Neuroprotective Agents / adverse effects
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Neuroprotective Agents / therapeutic use*
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Oxidative Stress
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Presenilin-1 / antagonists & inhibitors
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Presenilin-1 / genetics
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Presenilin-1 / metabolism
Substances
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Amyloid beta-Peptides
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Anti-Inflammatory Agents, Non-Steroidal
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Antioxidants
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Apolipoproteins E
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Nerve Tissue Proteins
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Neuroprotective Agents
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Presenilin-1
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presenilin 1, mouse
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Genistein
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse