Abstract
Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (CNS) insulin must first cross the blood–brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling.
Highlights
Rapamycin, known as sirolimus, is a compound that has been extensively studied for its impact on life span and health span across multiple species [1]
There was a decrease in the amount of 125I-insulin vascular binding (Vi) with the rapamycin injection, 10.1 ± 1.3 μL/g, compared to the vehicle, 11.1 ± 1.6 μL/g vehicle (p = 0.02, Table 1), which is indicative of alterations in the vascular binding sites for 125I-insulin
We investigated the effects of rapamycin treatment on the basal levels of insulin vascular binding, receptor signaling, and blood–brain barrier (BBB) pharmacokinetics in male and female mice
Summary
Known as sirolimus, is a compound that has been extensively studied for its impact on life span and health span across multiple species [1]. It primarily acts as an inhibitor of the ubiquitous signaling protein mammalian target of rapamycin (mTOR), which regulates growth and metabolism. There are many studies that have investigated the beneficial effect of rapamycin on life span extension, in relation to cognitive decline and Alzheimer’s disease. We hypothesized rapamycin would increase the amount of insulin BBB transport or affect the BBB interactions, which could be a mechanism for improved cognition. We included a group of mice that received a single, acute injection of rapamycin to determine if there were any acute effects on insulin BBB transport
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