The role of astrocytes in apoE4 related neurodegeneration.

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Alzheimer‘s disease (AD) is a neurodegenerative disorder with increasing incidence in the postindustrial world. Genetic causes as well as different predisposing factors have been discussed in the recent literature, pointing towards a multifactorial disease origin. A major genetic risk factor of familial and sporadic AD is apolipoprotein (apo) E4, one of the 3 apoE isoforms in humans with 65-80% of AD subjects being ApoE4 carriers. The molecular mechanisms underlying this association are not well understood, and no current therapies are based on apoE4 predisposition. Weisgraber et al from the Gladstone Institutes, San Francisco, determined unique changes in the structure of the apoE4 isoform that were predicted to affect its function: one such is domain interaction that leads to a compact protein structure. The group developed a mouse model that is selectively specific for domain interaction, the Arg-61 apoE mouse (model system in the present proposal). Studies in this model revealed that domain interaction in these mice leads to enhanced endoplasmic reticulum stress levels and induces astrocyte dysfunction, which consecutively might lead to impaired neuronal repair and maintenance. Animals exhibit cognitive dysfunction and learning disabilities similar to symptoms seen in AD. Thus, the contribution of Arg-61 apoE to neurodegeneration with a special focus on the role of astrocytes function will be examined in this proposal. Specific study aims will be 1) the direct dependence of astrocyte metabolism on Arg-61 apoE expression levels, 2) the possible role of Arg-61 apoE astrocytes as intrinsic components in the development of the Arg-61 apoE phenotype (cell autonomous vs. non cell autonomous contribution) 3) the significance of Arg-61 apoE as a predisposing factor for neurodegeneration in the presence of CNS insults. Insights in the mechanisms of apoE4/ Arg-61 apoE holds the potential open new therapeutic approaches in the treatment of a majority of AD subjects.