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.
Highlights
It is increasingly evident that obesity, diabetes mellitus, hypercholesterolemia, and nonalcoholic steatohepatitis (NASH) are associated with multiple aspects of brain pathogenesis [1,2,3]
We have previously reported that genistein alleviated NASH as well as hypercholesterolemia and obesity in Apolipoprotein E (ApoE)−/− mice fed a high-fat diet (HFD), suggesting that restoration of altered cholesterol metabolism and inhibition of oxidative stress and inflammation may be involved in the protective effect of genistein against NASH development [18]
We investigated the neuroprotective effect of genistein and its underlying mechanism in ApoE−/−
Summary
It is increasingly evident that obesity, diabetes mellitus, hypercholesterolemia, and nonalcoholic steatohepatitis (NASH) are associated with multiple aspects of brain pathogenesis [1,2,3]. Cardiovascular disease risk factors, such as hypercholesterolemia and oxidative stress, are involved in the development of cognitive dysfunction [4,5]. Alzheimer’s disease (AD), the most prevalent neurodegenerative disease in humans, is pathologically characterized by the extracellular deposition of beta-amyloid peptides (Aβ), the formation of intracellular neurofibrillary tangles due to an abnormal hyperphosphorylation of tau at specific epitopes, subsequent neuroinflammation, loss of synaptic plasticity, and neuronal death [6]. As the most cholesterol-rich organ, brain contains about one-fourth of the total body cholesterol for the use of dendritic formation and remodeling, and synaptic plasticity [5]. ApoE−/− mice have been used mostly for cardiovascular disease research [9], the underlying pathology of neurological disorders in ApoE−/−
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