|Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome.
|Year of Publication
|Johnson LA, Torres ERuth S, Impey S, Stevens JF, Raber J
|2017 03 08
|Animals, Apolipoprotein E4, Body Weight, Cognitive Dysfunction, Diet, High-Fat, Disease Susceptibility, DNA Methylation, Epigenesis, Genetic, Genotype, Glucose Intolerance, Hippocampus, Insulin Resistance, Metabolic Networks and Pathways, Metabolome, Mice, Models, Biological, Spatial Learning, Spatial Memory
Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer's disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.
|PubMed Central ID
|T32 DA007262 / DA / NIDA NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States
T32 HL094294 / HL / NHLBI NIH HHS / United States
R21 AG043857 / AG / NIA NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States