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 i nclude: 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.
