Alzheimer's Disease Research - Current Award

	Joachim Herz, M.D. The University of Texas Southwestern Medical Center at Dallas Dallas, TX Title: An Apoe Receptor-Mediated Mechanism For AD Pathogenesis Non-Technical Title: Apoe Receptors In Alzheimer's Disease Duration: April 1, 2009 - March 31, 2012 Award Type: Standard Award Amount: $400,000
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.

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.)

Progress Updates:

Genetic variations in Apolipoprotein E (ApoE) are the most important genetic risk factor for the most prevalent form of Alzheimer’s disease (AD), the late-onset form that typically manifests itself beyond the age of 65. The mechanisms by which ApoE is having this effect are poorly understood, and as a consequence, it has proven difficult to develop a potent drug to combat this severe neurodegenerative disease. In this project we are investigating how ApoE receptors, the proteins to which ApoE binds on the surface of the nerve cells, are involved in the Alzheimer’s disease process.

We are planning to investigate 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 structures that connect neurons with each other and allow them to communicate) and whether this affects synaptic functions; and iii) whether ApoE and the amyloid-beta peptide, which accumulates in the brains of Alzheimer’s patients, act synergistically to make the disease worse.

During the first year we have already made great progress on the second and the third aims, which have resulted in two published papers in the journal, Proceedings of the National Academy of Sciences. Together, both papers affirmatively answer questions 2 and 3 -- that ApoE and ApoE receptors (and other associated signaling proteins) modify nerve cell survival and affect the functions of the synapse. We will now refine our approaches to investigate whether we can find a pharmaceutical intervention that can prevent the deleterious effect of ApoE and thus hopefully protect patients from the late onset form of this disease.