Overexpressed amyloid precursor protein, and its C-terminal fragment, augment mitochondrial dysfunction in kidney and adipose tissues in a diet-induced obesity model

Abstract Amyloid precursor protein (APP) overexpression, and its induced mitochondrial dysfunction, is correlated with tissue stress or damage. The βC-terminal fragment (CTF) of APP has also been implicated in mitochondrial dysfunction however its overproduction in stressed or damaged tissue has rarely been reported. Here, we used long-term high fat diet exposure to inflict whole-body stress in a rodent model and evaluated APP and APP-βCTF level in a panel of tissues. We report that APP level was significantly increased by >2-fold in white adipose tissue and kidney tissue whereas liver and brain tissue levels remained unchanged. We report a significant increase in APP-βCTF level of 3-fold in visceral white adipose tissue and 0.8-fold in kidney tissue. Excess APP and APP-βCTF accumulated in the mitochondria from both adipose and kidney tissues and correlated with a significant reduction of complex I and IV enzyme activity of 53-78% and 70-90%, respectively, suggesting mitochondrial impairment. Lastly, our obese mice experienced elevated creatinine level suggesting initial kidney impairment which may explain the increase of APP in this tissue. Overall, APP upregulation, and a correlated increase in APP-βCTF, as causative agents of mitochondrial impairment, can occur in adipose and kidney tissue in a diet-induced obesity model.