Work

O1‐05‐01: APOE4 plays a role in Abeta‐mediated synapse loss in Alzheimer's disease

Year: 2011

Type: article

Abstract: The Apolipoprotein E (APOE) e4 gene is the most important genetic risk factor for late onset Alzheimer's disease (AD), but the link between APOE e4 and neurodegeneration remains unclear. Recent data from mouse models and cell culture has shown that oligomeric forms of amyloid-b are present at synapses where they contribute to synaptic dysfunction and loss, but the role of Ab in synapse loss in human AD and its relationship to APOE genotype remains an important question in the field. We have used size exclusion chromatography, confocal microscopy, and the advanced imaging technique array tomography in cell culture, mouse models, and human AD brain to test the hypothesis that APOE e4 acts through increasing levels of toxic oligomeric Ab (oAb) and targeting it to synapses. Using array tomography, we also explore the downstream effects of targeting oAb to synapses by examining the effects of oAb on synaptic composition. We find that APOE e4 substantially increases levels of oAb in the brain and increases association of oAb with synapses in the brain and in culture, indicating that APOE e4 may target oAb to synapses where it is toxic. Synapses contacted by oAb are abnormally small. APOE isoform has an effect on synapse loss with e4 associated with more synapse loss and more oAb at synapses. These data show that APOE4 enhances oAb's toxicity both by increasing oAb levels and by directing it to synapses where it causes shrinkage, changes in synaptic proteins, and ultimately synapse collapse. These results provide a link between APOE e4 genotype and synapse loss, the strongest correlate of cognitive decline in AD. These findings support the hypothesis that APOE e4 facilitates transport of oAb to synapses where it is toxic and further support the idea that oAb plays an important role in synaptic damage not only in animal models of Ab toxicity, but in human AD. Since synapses can reform after damage, blockade of the oAb-apoE interaction could be a therapeutic approach to preventing Ab mediated synapse loss in AD.

Source: Alzheimer s & Dementia

DOI: 10.1016/j.jalz.2011.05.256