Senior Scholar Award in Aging
Lawrence S.B. Goldstein, Ph.D.
University of California - San Diego, Howard Hughes Medical Institute

Probing the role of axonal transport disturbance and transport-mediated signaling in Alzheimer’s Disease

Neuronal degeneration and death are hallmarks of Alzheimer's Disease, but why they occur is still poorly understood. Most workers accept the hypothesis that degradation of a neuronal protein called Amyloid Precursor Protein (APP) is an early event in the pathogenesis of Alzheimer's disease (AD). Degradation of APP generates protein fragments that appear to aggregate and form the amyloid plaques that are one of the characteristic pathological features of AD. While some forms of hereditary AD are caused by mutations in the gene that codes for APP, we still do not know whether breakdown of APP is the initiating event in sporadic forms of AD and if so, why it occurs. Additional important holes in our understanding include knowledge of where in neuronal cells APP degradation takes place and why it might be neurotoxic.

Recent work in my lab and others has led to the idea that an aspect of neuronal biology that could play an important role in the development of AD is the extraordinarily large size of most neurons. As a result of their large size, many neuronal functions and signal transmission events have a critical dependence upon the physical movement of materials inside the cell. Our recent data suggest that an important normal function for APP is in the molecular transport machinery in neurons where APP may serve to link a particular class of cargo packages to a molecular motor protein called kinesin, which is responsible for the movement of these cargoes within the neuron from sites of synthesis to sites of use. Our data have suggested the testable hypothesis that deficits in this transport process may be intertwined with APP degradation and the development of AD, perhaps because of interference with signaling events critical for continued neuronal viability. Our work supported by the Ellison Medical Foundation is designed to explore and test this hypothesis using genetic and biochemical approaches in Drosophila and mouse.

Contact Dr. Goldstein.