期刊
BRAIN PATHOLOGY
卷 19, 期 1, 页码 69-80出版社
WILEY
DOI: 10.1111/j.1750-3639.2008.00174.x
关键词
Alzheimer's disease; hypercholesterolemia; neurodegeneration; N-methyl-D-aspartate receptor activity; Src kinase
资金
- Riksbankens jubileumsfond
- Swedish Brain Power project
- Loo och Hans Ostermans Stiftelse
- Gun och Bertil Stohnes Stiftelse
- Karolinska Institutets fund for geriatric research
- Ake Wiberg foundation
- Demensforbundet
- Alzheimerfonden
- Lars Hiertas minnesstiftelse
- Stiftelsen Gamla Tjanarinnor
- Dementia Foundation and Vetenskapsradet
- Spanish Foundation Alfonso Martin Escudero
Growing 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据