Alzheimer's Disease Research
Joachim Herz, M.D.
The University of Texas Southwestern Medical Center
Title: Reversing the APOE4 Risk for Alzheimer's Disease
Non-Technical Title: A Novel Therapeutic Approach to the Prevention of Alzheimer's Disease
Duration: July 1, 2013 - June 30, 2015
Award Type: Standard
Award Amount: $150,000
ApoE4 is the most important risk factor for Alzheimer’s disease. In previous work funded by BrightFocus Foundation, Dr. Herz’s team uncovered a molecular mechanism by which the ApoE4 protein likely manifests the disease risk by causing a traffic jam inside the nerve cells. Recently, the team discovered a conceptually innovative way to prevent this traffic jam using small molecules. They propose to develop this new discovery toward a preventive treatment for Alzheimer’s disease.
Dr. Herz’s team is investigating the biological and pathological mechanisms that underlie the traffic jam induced by ApoE4, the major risk factor for Alzheimer’s disease, in neurons, and are applying these insights toward the development of a novel treatment approach for this devastating neurodegenerative disease.
The team has identified an essential component of the neuronal endosome (one of the cell’s recycling centers) that is responsible for inducing a traffic jam that holds up the recycling of essential synaptic components in ApoE4 carriers. The synapse is the place where nerves communicate with each other, so a disruption of this function can lead to neurodegeneration. This novel target is amenable to pharmacological manipulation. The goal of this project is to establish a genetic proof-of-principle for this novel target by establishing a conditional animal model in which the gene that induces the traffic jam can be eliminated at will in an adult mouse brain. Dr. Herz’s team will then use their proven electrophysiological techniques to test whether the disruption of the gene, which they can also inhibit with drugs, is sufficient to restore normal function to the brain in the presence of ApoE4.
This proposal exploits an entirely novel conceptual molecular paradigm by which ApoE4 imposes increased risk for the development of late-onset Alzheimer's disease. In Dr. Herz’s earlier BrightFocus-funded research, they showed that ApoE4 impairs the recycling of ApoE receptors and associated glutamate receptors from excitatory synapses at the level of the early endosomes. From this insight, his team rationally deduced a novel method for therapeutic intervention, which is based on the manipulation of the conditions within the neuronal endosomes to resolve the ApoE4 induced “traffic jam.”
The intervention described above is amenable to orally available drug treatment and Dr. Herz has shown in vitro (at the lab bench) and in limited in vivo (animal) experiments that it has high potential to be effective and feasible in humans. The current proposal establishes the translational basis for moving these findings into drug discovery and pre-clinical and clinical trials.
Joachim Herz is the current Director of the Center for Alzheimer’s & Neurodegenerative Diseases, a Professor in Molecular Genetics at UT Southwestern Medical Center, and is the holder of the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer’s Disease Research. Alzheimer's disease and atherosclerosis are progressive degenerative syndromes that together afflict more than 50% of the population in Western societies. Their prevalence and socioeconomic impact is steadily increasing along with average life expectancy. Dr. Herz is noted for his groundbreaking research into how a mutation in a single protein triggers the devastation of Alzheimer’s disease, which affects 5.3 million Americans and is the country’s seventh-leading cause of death. Dr. Herz’s most recent work focuses on the study of molecules called APOE receptors, which are embedded in the membranes of nerve cells. APOE receptors serve as “signal modulators,” making the cells more responsive to incoming signals from other nerve cells, or neurons. The receptors can greatly change the sensitivity of neurons over the course of a single day, affecting how strongly nerve cells interact with each other.