NEW YORK -- The increased vulnerability to stress of brain cells in Alzheimer's disease results from changes in the level of specific protective proteins, report Japanese researchers.
Identification of these proteins, called chaperone proteins, may lead to
new therapies for Alzheimer's disease, according to Taiichi Katayama from Osaka
University in Japan, and associates. Their report is published in the December
issue of Nature Cell Biology.
Normal brain cells respond to various forms of stress by accumulating
unfolded proteins, the so-called unfolded protein response (UPR), the authors
explain. The increased level of unfolded proteins is then sensed by another
protein, the enzyme IRE1, which turns on the production of chaperone proteins.
These chaperone proteins foster the refolding of unfolded proteins to prevent
the cell death that might otherwise occur.
In one form of inherited Alzheimer's disease, abnormalities in the
presenilin-1 (PS1) gene result in changes in the UPR of brain cells. Unfolded
proteins accumulate to abnormal levels, making them much more susceptible to
cell death. These PS1 mutations result in much lower cell levels of the
protective chaperone proteins, the investigators report.
According to the researchers, PS1 interacts directly with IRE1 to prevent
activation of the chaperone proteins, thereby increasing the cell's
susceptibility to stressful stimuli.
The authors note that the levels of chaperone proteins were significantly
decreased in the brains of patients with sporadic Alzheimer's disease and even
more markedly decreased in the brains of those with PS1-linked Alzheimer's
disease.
Because the findings in patients parallel the changes seen in their
laboratory studies, the researchers suggest that the reduced levels of chaperone
proteins are likely to be associated with the abnormalities associated with
Alzheimer's disease.
Accordingly, the investigators propose that agents that increase the
activity of IRE1 or otherwise work to increase the levels of chaperone proteins
in the brains of patients with Alzheimer's disease may help to treat this
devastating disease.
