The sequence of the Alzheimer amyloid peptide (beta-protein) is part of the sequence predicted from at least three distinct cDNA species which derive from the same gene by alternative splicing. Each of the two longer forms of the amyloid peptide precursors (APP) contains at least one additional sequence of 56 residues. The mechanism by which beta-protein derives from APPs is not known. However, evidence suggests that APP may be a cell surface and/or a secreted protein. We have hypothesized that amyloid peptide may derive as a result of abnormal post-translational processing of the APP including dysfunctional endocytosis, lysosomal degradation, recycling of cell-surface APP, or glycosylation. Recent work indicates that the three forms of APP may be differentially expressed both in different mammalian brains and within different regions of the human brain. Specifically, it seems that in both normal and AD brains the insert containing APPS are present only in the regions involved in plaque formation. We propose to use anti-APP antisera to (a) describe the topographical expression of the different APP forms in normal and AD brains, (b) since the insert containing APP seems to be absent from the rodent brain, we would like to study the expression of the APP 751 in transgenic mice and (c) determine the proteolytic modifications, phosphorylation, membrane interactions, endocytosis and lysosomal degradation of the APP. Production of beta-protein could be due to abnormalities involving any one of these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005138-10
Application #
3768073
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
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