Project: Research project

Project Details


The overall objective of this proposal is to understand the role of the
amyloid precursor protein (APP) in the pathogenesis of amyloid deposition
in Alzheimer's disease (AD). AD which is characterized by deposition of
amyloid fibrils in neuritic plaques, cerebral vascular amyloidosis, and
neurofibrillary tangles within neurons is one of the most common causes of
dementia. While most cases of AD are sporadic, a significant number of
individuals are members of kindreds in which AD is inherited as an
autosomal dominant trait. The availability of these families allows for
study of AD in a controlled manner which may provide insight into
pathogenesis. In preliminary studies we have identified a mutation in the APP gene in
individuals with early onset hereditary AD. This mutation results in a
substitution of phenylalanine for valine in the transmembrane domain of
APP. We have been able to show inheritance of this mutation and
segregation with Alzheimer's disease. We propose to study the pathogenesis of AD in this family using both
molecular biology and protein chemistry techniques. Specific aims include:
1) complete characterization of the Val to Phe mutation by developing a DNA
test to screen individuals at risk, determine prevalence of the mutation in
the extended family, and complete the sequence of coding regions of the APP
gene in the affected proband; 2) extend the studies to other individuals
with Alzheimer's disease both familial and sporadic; 3) isolate amyloid
subunit protein from an affected member of this kindred and verify the size
of the subunit protein to determine whether the mutation is incorporated
into the fibrils; 4) study expression of the APP mutant. These specific
aims are formulated to test the hypothesis that this APP mutation is a
direct cause of amyloid deposition and presenile dementia in this family.
These studies may elucidate factors in pathogenesis that may have
application to other forms of Alzheimer's disease.
Effective start/end date7/1/926/30/98


  • National Institutes of Health: $18,469.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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