Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Lance A. Johnson, Eileen Ruth S Torres, Soren Impey, Jan F. Stevens, Jacob Raber

Research output: Research - peer-reviewArticle

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Abstract

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.

LanguageEnglish (US)
Article number43701
JournalScientific Reports
Volume7
DOIs
StatePublished - Mar 8 2017

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Apolipoprotein E4
Metabolome
Cognition
Insulin Resistance
High Fat Diet
Cognitive Dysfunction
Pentose Phosphate Pathway
Fat-Restricted Diet
Metabolomics
Apolipoproteins E
Metabolic Networks and Pathways
Type 2 Diabetes Mellitus
Dementia
Glutamic Acid
Alzheimer Disease
Protein Isoforms
Genome
Phenotype
DNA
Brain

ASJC Scopus subject areas

  • General

Cite this

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome. / Johnson, Lance A.; Torres, Eileen Ruth S; Impey, Soren; Stevens, Jan F.; Raber, Jacob.

In: Scientific Reports, Vol. 7, 43701, 08.03.2017.

Research output: Research - peer-reviewArticle

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