Please note: In general, we use our mouse model, the EFAD mice (5xFAD +/-/ APOE+/+) to determine the interactive effects of aging, APOE (E3FAD, E3/4FAD, E4FAD) and sex on the development of AD pathology. While many techniques overlap between projects, the main goal for rotation students is to understand the experimental design and interpret results from projects already available, as well as additional results generated by rotation students from on-going projects. Our readouts for AD pathology include neuronal viability (behavior, synaptic protein expression and neuronal loss), Aβ pathology, neuroinflammation and the solubility/aggregation of apoE and Aβ. Our techniques analyze behavior, immunohistochemistry (IHC) and biochemistry (BC).
- EFAD Mice as a Model for the Effects of APOE and Sex on AD Pathology
As part of our project to examine the interactive effects of aging, APOE genotype and sex on Alzheimer’s disease (AD) progression, rotation students will have the opportunity to interpret a massive data set from E2FAD, E3FAD and E4FAD mice aged 2-18 months.
- Estrogen Therapy as a treatment for APOE4-induced Pathology in Female EFAD Mice
We are part of a multi-PI grant to study the effect of estrogen therapy on AD pathology in ovariectomized EFAD (ε3/3, ε3/4 & ε4/4) mice replaced with estrogen, selective estrogen receptor modulators (SERMs) or selective estrogen mimics (SEMs) to mitigate the negative interaction of sex with ε4.
- Sex Differences in the Relationship Between APOE and AD: Role of Sexual Differentiation
We are part of a multi-center grant to determine the role of sexual differentiation in APOE4- and female sex-induced AD risk. EFAD mice are modified pre-natally (organizational stage) to produce a continuum of female, masculinized female, feminized male, and male mice. Combined with APOE genotypes ε3/3, ε3/4 and ε4/4, our focus to understand how the interactions between apoE lipidation and Aβ solubility affect the development and trajectory of AD pathology.
- ABCA1 as a Therapeutic Target for the Treatment of AD
ABCA1 is a cell-membrane lipid transporter that transfers intracellular lipid to nascent apoE-particles. As apoE4-particles are thought to be poorly lipidated compared to apoE3-particles, increasing the activity/function or transcription of ABCA1 seems a viable therapeutic target.
- We are currently on a pre-clinical project using cynomolgus monkeys to test an ABCA1 activator. Rotation students will learn to analyze peripheral lipoprotein profiles produced by size exclusion chromatography (FPLC) by measuring the lipid and protein content across the profile
- ABCA1 is a target for RXR agonists. Via a phenotypic screen to reduce toxic systemic effects and optimize expression in glial cells, we are testing the lead RXR agonist compound in EFAD mice to determine its effects on apoE lipidation and the development of AD pathology.
- Characterization of Protective Roles of APOE2 Against Alzheimer’s Disease
Using EFAD mice, we will determine how ε2/3,ε2/4 and ε2/2 interact with sex to modulate AD pathology. Little is known about the protective effects of APOE2 as the allelic variants are rare in a human population. For example, our hypothesis is that the protective effects of APOE2 will be greater in females compared to males.