Dr. William Mobley of the Department of Neuroscience at the University of California, San Diego is exploring important new avenues by which to understand the normal brain and the way it is impacted by Alzheimer’s disease and Down syndrome. His work is leading to new treatments and a better understanding of the biology behind these disorders. It is widely accepted that his laboratory leads the field in pursuing these conditions intelligently and aggressively, and they continue to produce outstanding and novel results. They are the largest lab dedicated to these pursuits, with the most researchers, and are one of very few labs whose focus is on the transport of trophic signals in these disorders. Their research is unique in that they explore the biology behind what goes wrong in individuals suffering from these conditions and how they can fix it - they have already made tremendous contributions in this narrow but important niche. Down syndrome is a condition that affect the quality of life of individuals, and Alzheimer’s is a disease that can drastically limit the lifestyle of individuals who have lived a previously full and healthy life. Uncovering therapies that reduce or reverse the effects of these challenges is an important medical focus, and one Dr. Mobley is at the forefront of attacking.

Within the brain, there are proteins released by neurons (brain cells) to help one another differentiate, grow, function, and thrive. These proteins are intended to weld neural circuits together and allow neurons to communicate, with one neuron releasing a signal and that signal binding to another neuron. In normal cells, such as a skin cell, the distance that signal needs to travel may be only a few microns (millionths of a meter) long; in neurons, the signal travels down the axon, which can be up to one meter in length. How then does the signal move down such a long distance? Research has shown that the answer is to package it and attach a “motor,” which takes the signal from the cell body of one neuron down the axon to the cell body of another neuron. This process is the Achilles’ heel of the neuron because this is the process every neural communication must undergo. It is a delicate communication process, and is potentially liable to falter in individuals with diseases that damage neural circuits, causing significant damage to intra-brain communication. Dr. William Mobley, Professor and Chair of the Department of Neurosciences at the University of California, San Diego is studying the basic genetic and molecular mechanisms that support the health and well-being of neurons and the events that compromise this in the context of Down syndrome and Alzheimer’s disease. The proteins belonging to the family “neurotrophins,” particularly nerve growth factor (NGF), which Dr. Mobley studied in graduate school, are believed to have an impact on the neurons damaged by Alzheimer’s disease, which also have applications for patients with Down’s syndrome, because all Down’s syndrome patients eventually develop the same brain changes as Alzheimer’s patients if they live long enough. The presence of extra APP in the brain, a naturally-occurring protein, interrupts neural communication, and Dr. Mobley is interested in understanding how the protein inhibits proper brain functioning and how that process can be corrected and/or reversed.

Dr. Mobley’s current research projects study the signaling of neurons and the applications in patients with Alzheimer’s and Down’s syndrome:

1.Dr. Mobley is researching basic normal biology of signaling in axons of cells in culture and normal animals. He is interested in answering: How does signaling occur? and What’s going on within the axon? Knowing that the axon is approximately a meter long, it would seem unlikely that a neuron would have to wait for the entire duration of time it takes the signal to travel through the axon to receive the signal communication. It is more likely that portions of the cell’s ability to code for proteins have been imported directly into the axon, enabling NGF to signal locally and allow a neuron to respond more rapidly to changes in its environment. This establishes a combined early initial response with the standard later response, increasing overall signaling ability.

2.Alzheimer’s disease and Down’s syndrome are being investigated to identify what goes wrong in these diseases: specifically, What are the proteins involved? What is going wrong with these proteins? and How can it be corrected? Recent findings point to changes in both the early responses to neurotrophin signals as well as those that are transmitted over the long distances traversed by axons. Understanding the biology of these diseases will pave the way for developing therapies that can prevent the negative effects of these diseases. There are essentially three leading approaches:

• Reducing the levels of excess APP protein by “turning down” the levels of active protein.
• Preventing the toxic forms of APP from compromising cellular activity by degrading the toxin more effectively and efficiently to eliminate the harmful effects.
• Solving the “transport problem” by modulating the activity of pathways impacted by the toxic forms of APP.

All of these approaches are targeted at aiding the cells being attacked by excess APP in Alzheimer’s and Down syndrome patients.

It was revealed through studying Down syndrome in cells in culture and animal models that in the brain there is normally a balance between neurons that electrically excite other neurons and those that electrically inhibit other neurons; in patients with Down syndrome, there is an excess of the inhibiting activity. Dr. Mobley is exploring the cause for this change and has evidence that APP and its toxic forms contribute. The search for additional genes that play a role is an important focus of research and excellent candidates have emerged.  This will support efforts to develop therapies to correct the imbalance. Indeed, it may be possible to orally deliver small molecules to reduce electrical inhibition thus releasing the brain circuits crucial for restoring a higher quality of life for individuals suffering from this condition.