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Traffic Jam on Axon Highway Occurs Early In Alzheimer’s, According to UCSD Team

 

September 22, 2005  |   

A blockage of the movement of chemical supplies and signals within the tube-shaped, brain-to-body cellular highways called axons, appears to occur much earlier than previously thought in the development of Alzheimer’s disease, according to research by the University of California, San Diego (UCSD) School of Medicine. The finding could lead to earlier diagnosis and may also provide insight into the causes of Alzheimer’s, a progressive, memory-robbing brain disorder affecting some 4.5 million Americans.

Published in the February 25, 2005 issue of the journal Science, the study was conducted in mouse models of Alzheimer’s disease and with brain tissue from human Alzheimer’s patients who had died when their disease was in its early stages.

The researchers found that abnormal amounts of proteins, organelles and vesicles had clogged up the axons – like a rock in a garden hose – in mouse models of Alzheimer’s almost a year before other disease-related symptoms were noted, and in the human tissue of early Alzheimer’s patients.

Axons are the long cellular highways that connect brain cells to each other and that carry electrical signals and chemical supplies throughout the brain. Axons extend long distances to their end points, called synapses; nerve impulses are transmitted via the axons so that thought, perception, memory, and learning can occur. Axons also extend to tissue such as muscle so that movements can be controlled by the brain. Although scientists have known that the transportation process within axons appeared blocked in late-stage Alzheimer’s patients, this study provides the first evidence that the process occurs early, perhaps even before the clinical signs of the disease are noticeable.

The findings also provide the first evidence of a mechanistic link between the two pathologies characteristic of Alzheimer’s brain tissue – twisted, insoluble brain fibers called neurofibrillary tangles, and amyloid plaques, which are excessive accumulation of protein fragments that the body produces normally. Previously, scientists have been unable to determine the molecular relationship between these two different characteristics.

“Proteins in both the tangles and plaque appear to be involved in transportation of materials within the axons,” said the study’s senior author Lawrence S.B. Goldstein, Ph.D., a UCSD professor of cellular and molecular medicine and a Howard Hughes Medical Institute investigator. “Tau, the protein in neurofibrillary tangles, is a protein that appears to regulate traffic within axons. Blockage within axons may promote the generation of excess amyloid beta, the protein in amyloid plaques.”

When the scientists evaluated the contents of axonal blockages, they found accumulations of haphazardly arranged vesicles, mitochondria and other organelles. Also prominent was an accumulation of kinesin-1, a protein that acts like a miniature truck to carry molecular cargo through the axons. An additional experiment showed that even a small reduction of kinesin is sufficient to impair axonal transport and promote abnormal amounts of amyloid beta.

“Our evidence suggests that axonal blockage does not form in response to amyloid deposition,” Goldstein said. “Rather, blockage seems to occur prior to amyloid deposition and other disease-related pathology. Thus, our findings suggest that axonal transport deficits play an early and potentially causative role in Alzheimer’s disease.”

The study was funded by the National Institutes of Health, the Ellison Medical Foundation, the Pew Foundation, the Boehringer-Ingelheim Fonds and the Howard Hughes Medical Institute. Additional authors included first author Gorazd B. Stokin, UCSD Department of Cellular and Molecular Medicine; and Concepcion Lillo, and David Williams, Ph.D., UCSD Department of Pharmacology; Tomas L. Falzone, Richard G. Brusch, and Stephanie L. Mount, UCSD Department of Cellular and Molecular Medicine; Edward Rockenstein, UCSD Department of Neurosciences; Rema Raman, UCSD Department of Family and Preventive Medicine; Peter Davies, Department of Pathology, Albert Einstein College of Medicine; and Eliezer Masliah, M.D., UCSD Departments of Neurosciences and Pathology.

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