Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

Abstract

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimers disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (A[beta]42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases A[beta]42, which is increased from adipose tissue of obese mice and is associated with higher plasma A[beta]42. Increasing circulating A[beta]42 levels in non-obese 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 levels of the closely related A[beta]40 isoform were increased. Administration of an A[beta] neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, A[beta] neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that A[beta]42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to A[beta]42 inhibited mitochondrial function. These data reveal a role for systemic A[beta]42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimers 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 obesityrelated 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.…”

“…A high‐fat diet can also increase whole brain and hippocampal Aβ levels in Tg2576 and APP/PS1 transgenic mice 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 .…”