Effects of leptin signaling on the development of Alzheimer's Disease pathology

Abstract

Alzheimer's Disease (AD) is the most common neurodegenerative disease associated with age. Hallmarks of AD pathology are the accumulation of amyloid plaques (containing Aβ) and fibrilization of the microtubule‐associated protein tau into tangles. Type II diabetes mellitus (T2DM) is a metabolic disorder commonly associated with obesity. Many individuals who suffer from T2DM develop resistance to leptin, a hormone released from adipose tissue to regulate food intake and energy metabolism. It has been observed that T2DM confers an increased risk for AD. Therefore, we set out to determine if a loss of leptin signaling affects AD pathogenesis. Previous data indicate that as plasma leptin levels rise, presenilin expression decreases along with total Aβ. To expand on these findings, a diabetic mouse line (db) was crossed with an AD mouse line (APP x PS1) to create a model to observe the effects of leptin resistance on levels of Aβ. In addition, AAV2/1 was used to express the tau mutant P301L in db mice to observe tau phosphorylation. Data were analyzed by western blot, ELISA, RT‐PCR, and IHC to detect pathologic Aβ and tau in the mouse brain. These data suggest that a deficiency in leptin signaling, as with leptin resistance, may promote AD pathogenesis. Future studies will focus on revealing the mechanism by which leptin modulates AD pathology. Supported by the CART Foundation and the Alzheimer's Association (IIRG‐10‐172905).