Abstract

The lifetime risk of developing Alzheimer’s disease (AD) varies from under 1% to over 60% according to apolipoprotein E (apoE) genotype; apoE is therefore the most significant common genetic risk factor for late onset AD, with the apoE4 isoform leading to an earlier onset of AD compared to the apoE3 isoform, and the apoE2 isoform being protective.

Early- and late-onset AD are pathologically similar conditions characterised by accumulation of the b-amyloid peptide as plaques. This peptide is generated from the amyloid precursor protein (APP) by presenilin. Mutations in either presenilin or APP lead to early onset AD.

We have identified a previously unstudied neuronal protein that has an isoform-specific binding to apoE3 and apoE4, forms a complex with APP and has a differential cellular interaction with normal versus pathogenic forms of APP . This interaction increases the production of b-amyloid [in press].

Here we present a model for the function of the Drosophila orthologue of this protein, that we call dementin. We show that dementin is necessary for normal brain development, and interacts both with human APP and with the Drosophila APP -like protein. Further, we show that neuronal disruption of dementin leads to neurodegeneration.

Our findings may therefore form a molecular link between established risk factors for early and late onset AD.