Abstract P2019: Diastolic Dysfunction In Alzheimer's Disease Is Associated With aβ- Amyloid Aggregate Formation And Mitochondrial Dysfunction

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease with memory impairment caused by an accumulation of toxic protein aggregates (Aβ- amyloid plaques and tau-derived neurofibrillary tangles). Several studies reported cardiovascular abnormalities with diastolic dysfunction in AD patients; however, the direct mechanism of cardiac dysfunction in AD patients remains unexplored. Therefore, we investigated the pathophysiological mechanism of cardiac dysfunction in the mice model of AD. Hypothesis: Two most commonly used mice models of AD was thoroughly evaluated for cardiac dysfunction, histopathology, and biochemical changes over aging. Methods and Result: To determine the mechanism of AD-associated cardiac dysfunction, we used two different AD mice models: double transgenic mice expressing a chimeric mouse/human amyloid precursor protein and a mutant human presenilin 1 (APP/PS1 Tg), and transgenic mice that is homozygous for a Psen1 mutation and the co-injected APPSwe and tauP301L transgenes (3xTg-AD). Cardiac function measurement using non-invasive echocardiography in aged Ntg and AD mice models showed no difference in systolic cardiac functional parameters. However, diastolic function assessment using Doppler echocardiographic measurements showed ventricular diastolic dysfunction with reduced diastolic filling in APP/PS1 Tg and 3xTg-AD mice. Western blot analysis showed Aβ- amyloid protein expression in APP/PS1 Tg hearts. Immunohistochemical and immunofluorescence staining of the APP/PS1 Tg heart sections further confirmed the Aβ- amyloid protein expression and Aβ- amyloid aggregate formation in the cardiomyocytes. Further evaluation of APP/PS1 Tg hearts demonstrated increased collagen deposition (Picro-Sirius red staining) and increased cardiomyocyte cross-sectional area. Interestingly, APP/PS1 Tg hearts also displayed mitochondrial dysfunction with decreased mitochondrial bioenergetics and significantly reduced mitochondrial function regulatory parameters. Conclusion: Overall, we found diastolic dysfunction development with Aβ- amyloid aggregate formation, fibrotic remodeling, increased cardiomyocyte cross-sectional area, and mitochondrial dysfunction in the AD mice hearts.