An ApoE Receptor-Mediated Mechanism For AD Pathogenesis
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.
(This study shows that Reelin, a natural and physiological ligand for ApoE receptors, functions as a neuromodulator in excitatory synapses where it potently counteracts the synapse suppressing effects of amyloid Beta.)
Basar Cenik, Chantelle F. Sephton, Colleen M. Dewey, Xunde Xian, Shuguang Wei, Kimberley Yu, Wenze Niu, Giovanni Coppola, Sarah E. Coughlin, Suzee E. Lee, Daniel R. Dries, Sandra Almeida, Daniel H. Geschwind, Fen-Biao Gao, Bruce L. Miller, Robert V. Farese, Jr., Bruce A. Posner, Gang Yu, and Joachim Herz. SAHA Suberoylanilide hydroxamic acid (vorinostat) upregulates progranulin transcription: a rational therapeutic approach to frontotemporal dementia. J. Biol. Chem. 286, 16101- 16108 (2011)
Herz J. Apolipoprotein E receptors in the nervous system. Curr Opin Lipidol. 2009 Jun;20(3):190-6. Review.
First published on: April 13, 2009
Last modified on: March 19, 2013