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

Abstract

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The role of amyloid beta 42 (Aβ42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ42. Increasing circulating Aβ42 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 Aβ40 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 Aβ42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ42 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.

Experimental laboratory models as tools for understanding modifiable dementia risk

“… 191 , 203 Interestingly, adipose tissue expresses and releases Aβ42 into circulation. 204 Some obesity‐related brain changes may be caused by dysregulation of adipokines such as leptin, which are secreted by adipose tissue and can influence plasticity, neurogenesis and inflammatory cytokine production in dementia‐relevant brain regions such as the hippocampus. 205 Studies in AD models have suggested that leptin may have a therapeutic role in reducing Aβ and intracellular tau phosphorylation, thereby preventing synaptic dysfunction.…”