Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro.
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.
Mateos
Laura
L
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Karolinska Institutet, Stockholm, Sweden.
Akterin
Susanne
S
Gil-Bea
Francisco-Javier
FJ
Spulber
Stefan
S
Rahman
Atiqur
A
Björkhem
Ingemar
I
Schultzberg
Marianne
M
Flores-Morales
Amilcar
A
Cedazo-Mínguez
Angel
A
D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019061:src-Family Kinases / Q000378:metabolism
C473930:ARHGEF26 protein, human; D003598:Cytoskeletal Proteins; D004041:Dietary Fats; D020662:Guanine Nucleotide Exchange Factors; D006888:Hydroxycholesterols; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; C582467:SGEF protein, mouse; C092069:activity regulated cytoskeletal-associated protein; D001127:Arginine Vasopressin; D012313:RNA; C076996:27-hydroxycholesterol; D019061:src-Family Kinases