Project: Research project

Project Details


DESCRIPTION: (Applicant's abstract) Alzheimer's disease (AD) is the major
cause of memory loss and dementia. Senile plaques and paired helical
filaments are pathological hallmarks of AD brains. A beta peptide, the
principal protein component of senile plaques, is generated by the
processing of amyloid precursor protein (APP). Understanding the molecular
mechanism whereby APP is processed to generate A beta peptide is crucial
to unraveling the mechanism of senile plaque. Alpha-secretase cleaves APP
in the middle of A beta peptide an , therefore, precludes its production.
The present project will focus on the cellular and molecular mechanisms by
which APP is processed by alpha-secretase. Our studies are based on our
recent report that indicated APP enrichment in caveolae, a specialized
domain on the cell surface membranes consisting of caveolins, where alpha-
secretase cleavage of beta-APP takes place. Specific aims will test the
following hypothesis: (1) Astrocytes possess caveolae and caveolin; (2)
Increased caveolin production in astrocytes will increase a alpha-
secretase processing of a Swedish beta-APP mutant found in FAD and; (3)
Caveolin expressing will increased wild-type beta-APP processing at an
alpha-secretase site on neuronal cells.

These studies will clarify the precise location of beta-APP processing by
alpha-secretase and may help develop a specific therapeutic strategy to
prevent AD. Augmentation of caveolin expression may provide a unique
approach to alter the processing pattern of beta-APP from the
amyloidogenic beta/gamma to the non-amyloidogenic alpha-secretase. These
studies would generate a new line of research for preventing the
generation of toxic amyloid peptide in vivo.
Effective start/end date10/1/989/30/99


  • National Institute on Aging


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