The role of ApoE genotype on blood-brain barrier functions

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OVERVIEW: The aim of the present project is to decipher the role of the apolipoprotein E (ApoE) genotype on blood-brain barrier (BBB) functions, using animal models and series of complementary in vivo technical approaches. BACKGROUND: The BBB controls the entry and exit of endogenous and exogenous compounds in the brain, thereby regulating brain homeostasis. Recent evidence indicates that brain function depends on ApoE genotype, possibly through alterations in functional and structural integrity of the BBB, but molecular mechanisms remain elusive. RECENT PROGRESS: In the last years, we accumulated preliminary data suggesting that important BBB-related parameters are critically affected by the ApoE genotype in ApoE2, E3, and E4 mice. SPECIFIC OBJECTIVES: BBB properties will be compared in mice specifically expressing human ApoE isoforms E2, E3, or E4. Technical approaches will combine in situ cerebral perfusion, immunofluorescence, Western immunoblotting and electron microscopy. Specific endpoints will include: cerebrovascular volume, BBB surface and permeability, brain capillary morphology and transporter function and expression. The novelty of our approach stems from the combination of quantitative and qualitative methodologies. CONCLUSION: The main expected 5-year deliverables of the present grant application are (i) the formation of graduate students with training on techniques pertaining to the BBB, which are available in just a few laboratories in the world, and (ii) a better understanding of the role of ApoE on BBB function in brain homeostasis.