Antisera to an amino-terminal peptide detect the amyloid protein precursor of alzheimer's disease and recognize senile plaques

The cerebral amyloid deposited in Alzheimer's disease (AD) contains a 4.2 kDa β amyloid polypeptide (AP) that is derived from a larger β amyloid protein precursor (APP). Three APP mRNAs encoding proteins of 695, 751, and 770 amino acids have previously been identified. In each of these, there is a single membrane-spanning domain close to the carboxyl-terminus of the APP, and the 42 amino acid AP sequence extends from within the membrane-spanning domain into the large extracellular region of the APP. We raised rabbit antisera to a peptide corresponding to amino acids 45-62 near the aminoterminus of the APP. We show that these antisera detect the APP by demonstrating that they (i) label a set of ∼120 kDa membrane-associated proteins in human brain previously detected by antisera to the carboxyl-terminus of APP and (ii) label a set of ∼120 kDa membrane-associated proteins that are selectively overexpressed in cells transfected with a full length APP expression construct. The APP_45-62 antisera specifically stain senile plaques in AD brains. This finding, along with the previous demonstration that antisera to the carboxyl-terminus of the APP label senile plaques, indicates that both near amino-terminal and carboxyl-terminal domains of the APP are present in senile plaques and suggests that proteolytic processing of the full length APP molecule into insoluble amyloid fibrils occurs in a highly localized fashion at the sites of amyloid deposition in AD brains.