ApoE Receptors In Alzheimer's Disease

Joachim Herz, MD
The University of Texas Southwestern Medical Center at Dallas (Dallas, TX)
Year Awarded:
2009
Grant Duration:
April 1, 2009 to June 26, 2012
Disease:
Alzheimer's Disease
Award Amount:
$400,000
Grant Reference ID:
A2009041
Award Type:
Standard
Award Region:
US Southern

An ApoE Receptor-Mediated Mechanism For AD Pathogenesis

Summary

We have identified a novel conceptual mechanism by which ApoE and amyloid beta peptide interact at the level of the synapse. This mechanism has the potential to explain the fundamental molecular pathways that underlie the causes of Alzheimer's disease. Understanding of these mechanisms may open a new door to effective, rational drugs designed to work against Alzheimer's disease.

Details


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.

Research Updates

Dr. Herz’s team is investigating how Apolipoprotein E receptors, the proteins to which ApoE binds on the surface of the nerve cells, are involved in the Alzheimer’s disease process. The team is investigating three related questions: i) whether genetic interactions between ApoE and ApoE receptors modify nerve cell survival in genetically mutated mice; ii) whether ApoE and ApoE receptors interact at the level of the synapse (i.e. the organelles that connect neurons with each other and through which nerve signals are transmitted), and whether this affects synaptic functions; and iii) whether ApoE and the beta-amyloid peptide, which accumulates in the brains of Alzheimer’s patients, act synergistically to make the disease worse. The team made great progress on the second and the third aim, which have resulted in a published paper in the Proceedings of the National Academy of Sciences and a second manuscript that is currently being peer-reviewed. Together, both papers affirmatively answer questions 2 and 3—that is, the genetic interactions between ApoE and its receptor do affect synaptic functions, and ApoE and beta-amyloid act synergistically to make the disease worse. Dr. Herz’s team will now investigate whether they can find a pharmaceutical intervention that can prevent the deleterious effect of ApoE, with the future goal of protecting patients from the late onset form of this disease.

Publications

Durakoglugil, M., Chen, Y., White, C., Kavalali, E., and Herz, J. (2009) Reelin signaling antagonizes beta-amyloid at the synapse. PNAS 106,15938-15943  

(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) PubMed Icon Google Scholar Icon

Herz J. Apolipoprotein E receptors in the nervous system. Curr Opin Lipidol. 2009 Jun;20(3):190-6. Review. PubMed Icon Google Scholar Icon
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