Alzheimer's disease is occurring with increasing prevalence in part due to the increasing number of elders in the US and throughout the world. Despite extensive efforts, the development of therapies for this debilitating disease have been disappointing to date. Interestingly, numerous studies show that the mTOR pathway is elevated in human AD tissue and mouse AD models, and moreover that reducing mTOR activity with rapamycin (at least in the mouse models) reduces AD pathology. An individual's ApoE allele highly influences their risk of AD, and recent mouse models recapitulate these findings. One striking feature of both mTOR and ApoE is that they are both also linked to normal aging. Here, we propose that they may be functionally related and seek to assess in the 5XFAD mouse model whether reduced mTOR signaling is sufficient to rescue AD pathology associated with expression of ApoE4. Another poorly understood feature of AD is that pathology is often more severe in females. This is relevant to mTOR signaling as well, since we have shown sexual dimorphism associated with mTOR signaling and age and further that reducing the activity of downstream substrates has sex-specific benefits. In this proposal, we will test the hypothesis that different mTOR signaling underlies sex-specificity in AD pathology. Together these studies will uncover mechanistic connections between factors clearly implicated in Alzheimer's disease and further shed light on the potential therapeutic benefits of modifying mTOR signaling.

Public Health Relevance

Several proteins and cellular signaling pathways have been linked to Alzheimer's disease (AD) onset and severity, including the mTOR pathway and the ApoE protein. However, little is known about how these pathways interact. In this proposal, we assess whether ApoE and the mTOR pathway interact in a mouse model of AD and also determine links between mTOR signaling and the enhanced pathology evident in females with the disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fridell, Yih-Woei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Buck Institute for Age Research
United States
Zip Code
Liao, Chen-Yu; Anderson, Sydney S; Chicoine, Nicole H et al. (2017) Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins. Cell Discov 3:17039
Tsai, Shih-Yin; Rodriguez, Ariana A; Dastidar, Somasish G et al. (2016) Increased 4E-BP1 Expression Protects against Diet-Induced Obesity and Insulin Resistance in Male Mice. Cell Rep 16:1903-14
Kennedy, Brian K; Lamming, Dudley W (2016) The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab 23:990-1003