Project name: Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

Description: There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (Ab42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Ab42, which is increased from adipose tissue of obese mice and is associated with higher plasma Ab42. Increasing circulating Ab42 levels in mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating Ab40 levels were increased. Administration of an Ab neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Ab neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that Ab42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to Ab42 inhibited mitochondrial function. These data reveal a role for systemic Ab42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure.Overall design: This series consists of two components that were conducted separately. In part 1 of this study, C57BL6 mice were treated with Aβ42, an amyloid beta peptide of 42 amino acids, or a scrambled Aβ42 sequence at a dose of 1mg/day i.p. In the second part of the study, C57BL6 mice given Aβ42 were additionally treated with a Aβ42 neutralising antibody called 3D6 or a control antibody.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2022-09-19