Activity‐Regulated Cytoskeleton‐Associated Protein in Rodent Brain is Down‐Regulated by High Fat Diet in vivo and by 27‐Hydroxycholesterol in vitro

Brain Pathology - Tập 19 Số 1 - Trang 69-80 - 2009
Laura Mateos1, Susanne Akterin2, Francisco J. Gil‐Bea2, Ştefan Spulber3, Mohammad Atiqur Rahman2, Ingemar Björkhem4, Marianne Schultzberg3, Amilcar Flores‐Morales5, Ángel Cedazo‐Mínguez2
1Department of Neurobiology, Care Sciences and Society, Karolinska Institutet‐Alzheimer's Disease Research Center, Karolinska Institutet, Stockholm, Sweden
2Department of Neurobiology, Care Sciences and Society, Karolinska Institutet‐Alzheimer's Disease Research Center,
3Department of Neurobiology, Care Sciences and Society, Division of Neurodegeneration and Neuroinflammation, and
4Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, Sweden
5Dept. of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Tóm tắt

AbstractGrowing evidence strongly suggests that high fat diet (HFD) has an important role in some neurodegenerative disorders, including Alzheimer's disease (AD). To identify new cellular pathways linking hypercholesterolemia and neurodegeneration, we analyzed the effects of HFD on gene expression in mouse brain. Using cDNA microarrays and real time RT‐PCR, we found that HFD has a mild, but significant effect on the expression of several genes. The altered genes include molecules linked to AD pathology and others of potential interest for neurodegeneration. We further investigated the effect of HFD on the activity‐regulated cytoskeleton‐associated protein (Arc). Expression of Arc was decreased in cerebral cortex and hippocampus of HFD‐fed animals. From the known regulatory mechanisms of Arc expression, HFD reduced N‐methyl‐D‐aspartate receptor (NMDAR) activity, as seen by decreases in tyrosine phosphorylation of NMDAR2A and levels of NMDAR1. Additionally, we demonstrated that 27‐hydroxycholesterol, a cholesterol metabolite that enters the brain from the blood, decreases Arc levels as well as NMDAR and Src kinase activities in rat primary hippocampal neurons. Finally, we showed that Arc levels are decreased in the cortex of AD brains. We propose that one of the mechanisms, by which hypercholesterolemia contributes to neurodegenerative diseases, could be through Arc down‐regulation caused by 27‐hydroxycholesterol.

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Brain Pathology

Tập 19 Số 1

69-80

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