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.
Digital Object Identifier (DOI)
L.A.J. was supported by NIEHS grant T32-ES07060, NIH grant T32-HL094294, NSF grant SMA-1408653, an OHSU Tartar Award, the Oregon Tax Check-off Program for Alzheimer’s Research administered by the Layton Aging & AD Center at OHSU, the Collins Medical Trust of Portland, OR, and the OHSU development account of J.R. N.A. was supported by NIH R21AG043857. J.F.S. was supported by NIH grant S10RR027878 and the OSU Mass Spectrometry Core Facility of the Environmental Health Sciences Center grant P30ES000210.
Supplementary information accompanies this paper at http://www.nature.com/srep
Johnson, Lance A.; Torres, Eileen Ruth S.; Impey, Soren; Stevens, Jan F.; and Raber, Jacob, "Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome" (2017). Physiology Faculty Publications. 112.