ApoE4 is a major risk factor for late onset Alzheimer?s disease. In the CNS, ApoE is mainly produced by astrocytes. ApoE is a complex of ApoE apolipoprotein, phospholipids, and cholesterol. A major role of the ApoE/lipid complex in the brain is to deliver cholesterol and other lipids to neurons and other cell types for utilization. The lipid complex formed with ApoE4 contains less cholesterol than those formed with ApoE2 or ApoE3. ApoE4 also leads to malfunctions in N-methyl-D-aspartate receptor (NMDAR) mediated signaling in the hippocampus and in the cortex. We hypothesize that these malfunctions caused by ApoE4 can be ameliorated by selectively increasing cholesterol synthesis in the astrocytes and/or in the neurons in vivo. To test our hypothesis, we will carry out three specific aims.
Specific Aim 1. To establish a sensitive procedure to monitor relative cholesterol synthesis rates in astrocytes and neurons of the hippocampal region ex vivo. (Year one) Specific Aim 2.To establish a recombinant adeno-associated virus-mediated inducible gene expression in tSREBP2 that produces selective increase in cholesterol synthesis in astrocytes or in neurons. (Year one) Specific Aim 3A-To monitor relative cholesterol synthesis rates in astrocytes and neurons in the hippocampal region ex vivo before and after selective tSREBP2 gene expression occurs in vivo. (Year two) Specific Aim 3B-To monitor NMDAR dependent synaptic plasticity in acute hippocampal slices before and after selective tSREBP2 gene expression occurs in the hippocampal region in vivo. (Year two) ! 1!
Alzheimer?s disease (AD) is a major neurodegenerative disease with no cure at present. ApoE4 is a major risk factor for late onset AD. Within the biomedical research community, a popular view is that too much cholesterol is not good for human health. The outcome of our proposal may provide a paradigm shift: in AD patients with the ApoE4 genotype, agents that increase cholesterol biosynthesis in selective region of the brain may actually ameliorate the disease. !
