Role of E4orf1 protein in preventing the progression of cognitive and synaptic dysfunction in mouse model of Alzheimer’s disease



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Alzheimer’s disease (AD) is the sixth leading cause of death and is correlated with obesity, the second leading cause of preventable diseases in the United States. Obesity, Type 2 diabetes (T2D), and AD share several common features, and impaired metabolism and inflammation emerge as the central link. Progressive aging and high-calorie intake, elevated free fatty acids, and impaired endocrine function leads to insulin resistance and systemic inflammation. Systemic inflammation triggers neuroinflammation, which eventually hinders the metabolic and regulatory function of the brain mitochondria leading to neuronal damage and subsequent AD-related cognitive decline.

AD is associated with obesity and impaired glycemic control, and it has been shown that in the AD mice model, glycemic impairment and insulin resistance persist long before cognitive decline. Therefore, reducing hyperinsulinemia or improving glycemic control could be an effective treatment strategy for preventing AD-related cognitive functioning. Considering the association between T2D and AD, several anti-diabetic drugs have been tested, but only show modest improvement. Unfortunately, proximal insulin resistance is a hallmark of T2D, making many anti-diabetic drugs ineffective as they require functional insulin signaling for their action. Therefore, a drug that can improve T2D independent of insulin resistance and have the ability to improve cognitive function is much desirable. E4 open reading frame 1 (E4orf1) is an adenovirus derived protein that promotes glucose clearance independent of insulin, lowers serum insulin needs, and improves glycemic control could be one of the potential candidates. In this study, we evaluated if the anti-diabetic potential of E4orf1 can enhance cognitive function and AD-related alteration in a mouse model of AD.

The transgenic APP/PS1 mouse model exhibits AD-related cognitive and mitochondrial pathogenesis as early as 6-9 months. We generated APP/PS1/E4 “triple transgenic” mice via cross breeding APP/PS1 mice with transgenically express E4orf1 in the adipose tissue upon feeding doxycycline in the diet. To test improved cognition and AD-associated mitochondrial pathogenesis by E4orf1, we exposed APP/PS1/E4 mice to doxycycline supplemented high-fat diet (HFD, 60% kcal from fat) for 10-weeks followed by doxycycline containing chow diet for an additional 10-weeks. Body composition, blood glucose, and serum insulin were measured at 14th weeks of experimental feeding. Cognition data was collected at the end of the study before sacrifice. We also compared mRNA and protein markers of adipose tissue, liver lipid metabolism, and AD pathogenesis-related markers in the brain.

E4orf1 expression in transgenic APP/PS1 mice showed no changes in body weight but decreased % body fat and increased the % Fat-free mass upon HFD followed by chow diet. Both groups of mice remained normoglycemic; however, the need for insulin to clear the glucose load was significantly lower in E4orf1 expressing mice. E4orf1 expressing mice showed significant improvement in liver lipid metabolism, evidenced by a reduction in de novo lipogenesis and increased Triglycerides transport. mRNA and protein markers in adipose tissue also suggested a reduced de novo lipogenesis and increased oxidation. E4orf1 expression in APP/PS1 mice is able to rescue the spatial memory deficits as determined by Morris water maze cognitive testing. E4orf1 expression in APP/PS1 mice also showed improvement in synaptic and mitochondrial genes in the hippocampus and cortex. It also rescued the AD-related impairments in neurogenesis and glucose metabolism. However, no significant difference between the two groups was observed at the protein level. E4orf1 expression in APP/PS1 was not able to improve the amyloid beta (Aβ) plaque burden, which is one of the prominent pathological markers in the AD brain; however, E4orf1 reduced the Aβ mass in serum. E4orf1 expression exhibited moderate improvements in the clearance of Aβ in the brain tissue evidenced by increasing Aβ degrading enzyme neprilysin, although the exact mechanism is unknown.

In summary, the data suggest that improvement in glycemic control by E4orf1, without increasing endogenous insulin secretion, prevents cognition decline and mitochondrial dysfunction in APP/PS1 mice.

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Alzheimer's diseases, Inflammation, E4orf1 protein, Synaptic dysfunction, Cognitive decline