Synergistic patterned neurodegeneration by APP and APOE4

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PROJECT SUMMARY Alzheimer disease (AD) is the most common cause of dementia and the 6th leading cause of death in the US, but the precise etiology of AD is unclear. Some cases of AD are clearly linked to the amyloid precursor protein (APP) gene which encodes a protein that is broken into toxic peptides and peptide aggregates that form plaques. Most cases of AD, however, are linked to a specific variant of the apolipid E (APOE) gene; over 40% of people with AD carry APOE4 and those who carry two APOE4 alleles have greater than 90% life-time risk of developing AD. Although APP has received intense study over several decades, it remains uncertain how APP leads to patterned neurodegeneration, and moreover how APOE4 synergizes with APP to contribute to AD. Important progress is being made with mouse models of AD; however, these approaches are often limited by the two years required for mice to display degeneration. To speed discovery, the Pierce-Shimomura lab recently developed a novel APP-related neurodegeneration model using the nematode C. elegans. The model expresses human APP pan- neuronally and intriguingly displays degeneration of specific subsets of neurons as the worm ages within only one week. This patterned neurodegeneration mimics an important hallmark of AD in humans in which neurodegeneration preferentially effects certain cholinergic neurons in brain regions associated with memory. The model also mimics an important aspect of human AD in that APP-induced neurodegeneration is accelerated by expressing APOE4, but not APOE3. Using cell-specific proteomics and the model of APP-related neurodegeneration in C. elegans, they aim to shed light on the molecular basis of patterned neurodegeneration in AD. Their approach addresses two critical questions in AD research: Why do specific neurons die? How does APOE4 increase risk of neurodegeneration? Finally, how does targeting a novel ligand, the sigma 2 receptor, conserved in worms and humans with small molecules relieve neurodegeneration? Knowledge gained from study in the C. elegans APP model can then be used to generate novel hypotheses to be tested in mammalian models of AD and may lead to novel therapeutics to treat AD.