An ApoE Receptor-Mediated Mechanism For AD Pathogenesis

Project Summary

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder. Its frequency and socioeconomic importance is growing exponentially along with the increasing lifespan of the human population. While the particularly vicious early-onset form of the disease is typically caused by point mutations in one of three known genes, including the amyloid precursor protein (APP) and the so-called presenilins, we currently estimate that at least 20 other genes contribute to a variable degree to the much more common late-onset form of Alzheimer's disease (LOAD). Of these late-onset genes, Apolipoprotein E (ApoE), is by far the most important risk factor for LOAD, owing to the frequent occurrence of the disease-associated ApoE-E4 variant in the human population. Although it was discovered over 15 years ago, the molecular mechanisms by which this cholesterol transport protein promotes neurodegeneration and accelerates the onset of Alzheimer's disease remains a mystery. In our studies to understand the underlying biochemical basis we have discovered pivotal functions for ApoE receptors, the proteins to which ApoE binds at the surface of neurons, in the developing embryonic brain, as well as in the synapses of the mature central nervous system. In this project we propose to 1) combine the power of genetics in mice with 2) sophisticated electrophysiological approaches to explore how 3) ApoE4, through interaction with its receptors, might differentially weaken the synapses and thereby cause the premature death of neurons in the most frequent form of AD. Understanding this mechanism is essential for the rational development of novel and effective approaches to prevent onset and progression of Alzheimer's dementia.