Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity.

Liam G Hall; Juliane K Czeczor; Timothy Connor; Javier Botella; Kirstie A De Jong; Mark C Renton; Amanda J Genders; Kylie Venardos; Sheree D Martin; Simon T Bond; Kathryn Aston-Mourney; Kirsten F Howlett; James A Campbell; Greg R Collier; Ken R Walder; Matthew McKenzie; Mark Ziemann; Sean L McGee
There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer's disease. The role of amyloid beta 42 (Aβ<sub>42</sub>) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ<sub>42</sub>, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ<sub>42</sub>. Increasing circulating Aβ<sub>42</sub> levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ<sub>40</sub> isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ<sub>42</sub> impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ<sub>42</sub> inhibits mitochondrial complex I. These data reveal a role for systemic Aβ<sub>42</sub> 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.
ISSN 2041-1723
Published 15 Jan 2024
Volume 15
Issue 1
Pages 258
DOI 10.1038/s41467-023-44520-4
Type Journal Article