Reversing the APOE4 Risk for Alzheimer's Disease
ApoE4 is the most important risk factor for Alzheimer’s disease. In previous work funded by BrightFocus, Dr. Herz’ 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.