DHA Brain Delivery by APOE Genotype (Animal)

  • The objective of this particular project is to test whether brain ApoE lipidation differentiates APOE ɛ2 from APOE ɛ4 variant.
  • We are interested in how ApoE HDL in the brain regulates the metabolism of the omega-3 (ω-3) polyunsaturated fatty acid docosahexaenoic acid (DHA).
  • We recently demonstrated that in patients with mild AD, APOE ɛ2 carriers have greater cerebrospinal to plasma DHA ratio compared with APOE ɛ4 carriers. After 18 months of DHA supplementation, APOE ɛ4 carriers had less delivery of DHA to the brain compared with non-carriers. Using [11C]-DHA PET, we demonstrated that younger APOE4 carriers have a deficit in brain DHA compared with non-carriers. (DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA.)
  • We hypothesize that reduced ApoE4 lipidation underlies the changes in DHA brain delivery in the context of APOE ɛ4 genotype. To test our hypothesis, we propose mechanistic studies to identify DHA transport by ApoE HDL both in vivo and in vitro.
  • Using the ApoE mimetic peptide CS-6253, we will test whether enhancing the lipidation of ApoE4 proteins would enhance the delivery of DHA to the brain in APOE4 mice.
  • In Aim 2, we develop a novel PET imaging technique for assessing [18F]-DHA brain uptake.

Project Funding: DHA Brain Delivery by APOE Genotype (Animal)