Project: Research project

Project Details


Alzheimer's disease is a common, progressive, incurable and
ultimately fata disease of the central nervous system. At the
histopathological level it is characterized by the formation of
neurofibrillary tangles (NFT) and senile plaques (SP). At the
ultrastructural level, unusual highly insoluble paired helical
filaments (PHF) are detected. We have recently shown that
brains from patients with Alzheimer's disease exhibit striking and
unusual ubiquitin immunoreactivity on neurofibrils in regions
containing NFT and SP. Very small numbers of ubiquitin
immunoreactive neurofibrils are seen in normal aged brain, and
such profiles are absent from younger healthy brain tissue. In
preliminary experiments we have defined a proteolytic fragment
from paired helical filament (PHF) preparations, believed to be
the essential constituents of NFT, which has ubiquitin
immunoreactivity, but which is much larger than ubiquitin. This
must be derived from a protein in PHF fractions which is
ubiquitinylated. We wish to follow up these interesting

We will:

1) use immunlogical, biochemical and molecular biological
techniques to identify the parent molecule from which the
ubiquitin-immunoreactive proteolytic fragment is derived. We
will then know if this protein is present or absent in normal brain,
and if it is present, if it corresponds to a normal cellular protein.

2) study the distribution of ubiquitin immunoreactivity,
immunoreactivity for the ubiquitin acceptor protein, and
immunoreactivity for other known or putative NFT markers to
build up a comprehensive view of the relationship of each of these
markers to one another in NFT and PHF.

These studies will define in molecular terms an ubiquitinylated
component of NFT and will set the stage for an examination of
the mechanisms of PHF formation, the significance of
ubiquitinylation in PHF formation, and the reasons why the
ubiquitinylated NFTs are not degraded.
Effective start/end date1/1/901/1/90