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