Amyloid Precursor Protein Revisited NEURON-SPECIFIC EXPRESSION AND HIGHLY STABLE NATURE OF SOLUBLE DERIVATIVES

APP processing and amyloid-beta production play a central role in Alzheimer disease pathogenesis. APP has been considered a ubiquitously expressed protein. In addition to amyloid-beta, alpha- or beta-secretase-dependent cleavage of APP also generates soluble secreted APP (APPs alpha or APPs beta, respectively). Interestingly, APPs beta has been shown to be subject to further cleavage to create an N-APP fragment that binds to the DR6 death receptor and mediates axon pruning and degeneration under trophic factor withdrawal conditions. By performing APP immunocytochemical staining, we found that, unexpectedly, many antibodies yielded nonspecific staining in APP-null samples. Screening of a series of antibodies allowed us to identify a rabbit monoclonal antibody Y188 that is highly specific for APP and prompted us to re-examine the expression, localization, and stability of endogenous APP and APPs beta in wild-type and in APPs beta knock-in mice, respectively. In contrast to earlier studies, we found that APP is specifically expressed in neurons and that its expression cannot be detected in major types of glial cells under basal or neuroinflammatory conditions. Both APPs alpha and APPs beta are highly stable in the central nervous system (CNS) and do not undergo further cleavage with or without trophic factor support. Our results clarify several key questions with regard to the fundamental properties of APP and offer critical cellular insights into the pathophysiology of APP.