Evidence of Increased Prefrontal Cortex Inflammation and Amyloid Precursor Protein Processing in a Translational Swine Model of Heart Failure with Preserved Ejection Fraction

The oligomerization of amyloid beta peptides (Aβ), a histopathological hallmark of diseases such as Alzheimer's, may be elevated in cardiogenic dementias coincident with heart failure (HF). BACE1, the rate‐limiting protease enzyme in the amyloidogenic process, initiates the processing of amyloid precursor protein (APP) leading to the production of Aβ. Understanding the mechanistic regulation of BACE1 may be critical for improving treatment efficacy in heart failure patients exhibiting cardiogenic dementia. The purpose of this study was to examine the molecular mechanisms of cardiogenic dementia in a novel swine model of HF with preserved ejection fraction (HFpEF) exhibiting comorbidities including obesity and metabolic syndrome. Female Ossabaw pigs were randomly divided into two groups; control (CON, n=4) and Western diet‐induced obesity/metabolic syndrome with pressure overload‐induced HFpEF (HF, n=4). The HF group was placed on a Western diet (starting at 3 mo. of age) and aortic‐banded (at 6 mo. of age) prior to euthanasia (at 12 mo. old). At euthanasia, prefrontal cortex and hippocampus regions were collected for Western blot analysis. Total body mass was increased (CON=42±2 vs. HF=72±4 Kg; p<0.01), but brain mass was decreased (CON=110±3 vs. HF=92±2 g; p<0.01) in the HF group. The HF group exhibited greater prefrontal cortex total APP (p<0.01), BACE1 (p<0.01) and CTF protein levels (p=0.01), indicative of increased APP processing. This was accompanied by increased markers of chronic stress and neuroinflammation, specifically phosphorylation of JNK (p<0.01) and phosphorylation of ERK (p<0.01). Aberrant control of the insulin‐signaling pathway was also observed in the prefrontal cortex via increases in the phosphorylation of Akt serine 473 (p<0.01) and insulin‐degrading enzyme protein content (p=0.03) in the HF group. Similar results were observed in the hippocampus for increases in APP processing (increased APP and CTF content), neuroinflammation (phosphorylation of JNK and ERK). However, there were no changes in BACE1 content or the insulin‐signaling pathway, highlighting the importance of examining regional differences in the brain. These data reveal that inflammatory stress and aberrant control of insulin signaling may be implicated in the pathogenic regulation of amyloid beta peptide metabolism in an experimental, large animal setting of HFpEF, and potentially contribute to the cardiogenic dementia often observed in HF patients. Support or Funding Information NIH R01 HL112998, PI: CAE NIH K01 HL125503 – PI, Padilla American Heart Association #16POST2776005, PI: TDO University of Missouri Research Board – PI's, Emter and Rector Alzheimer Society of Brant, Haldimand, Norfolk, Hamilton, and Halton, PI: REKM This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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