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

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.

Từ khóa


Tài liệu tham khảo

10.1083/jcb.200501156

10.1111/j.1471-4159.1982.tb07930.x

10.1016/j.neubiorev.2004.03.004

10.1016/0014-2999(91)90584-D

10.1161/01.ATV.0000120374.59826.1b

10.1111/j.1582-4934.2001.tb00159.x

10.1042/bj3290373

10.1016/j.brainres.2006.05.086

10.1212/01.WNL.0000125323.15458.3F

Franklin KBJ, 1997, The Mouse Brain in Sterotaxic Coordinates

10.1002/neu.480250309

10.1002/1531-8249(200007)48:1<77::AID-ANA12>3.0.CO;2-A

10.1172/JCI200522710

10.1038/nn779

10.1523/JNEUROSCI.20-11-03993.2000

10.1194/jlr.M300320-JLR200

10.1194/jlr.M500024-JLR200

10.1212/WNL.45.6.1092

10.1016/S0140-6736(00)03155-X

10.1002/ana.410420514

10.1038/5009

10.7326/0003-4819-137-3-200208060-00006

10.1016/S0006-8993(98)00730-6

10.1038/nrn2153

10.1212/WNL.57.8.1447

10.1073/pnas.92.12.5734

10.1006/meth.2001.1262

10.1016/0896-6273(95)90299-6

10.1073/pnas.0504436102

10.1194/jlr.M600529-JLR200

10.1385/MN:27:1:1

10.1016/j.bbr.2006.09.010

10.1212/WNL.41.4.479

10.1016/0896-6273(91)90375-A

10.1016/S0021-9150(98)00331-1

10.1159/000026149

10.1523/JNEUROSCI.2829-05.2005

10.1016/j.neuron.2006.08.024

10.1016/j.febslet.2005.10.024

10.1038/nn1708

10.3109/13506129909007315

10.1002/cne.10449

10.1002/ana.10292

10.1038/nn1503

10.1073/pnas.131146398

10.1016/S0896-6273(01)00275-6

10.1073/pnas.091062498

10.1111/j.1471-4159.2005.03378.x

10.1006/exnr.2001.7630

10.1001/archneur.60.1.16

10.1001/archneur.57.10.1439

10.1523/JNEUROSCI.22-05-01532.2002

10.1515/REVNEURO.2005.16.2.123

Thông tin
Thông tin xuất bản

Brain Pathology

Tập 19 Số 1

69-80

Thông tin tác giả