HUMAN NEUTROPHIL PHAGOCYTIC GRANULES CONTAIN A TRUNCATED SOLUBLE FORMOF THE ALZHEIMER BETA A4 AMYLOID PRECURSOR PROTEIN (APP)/

We have characterized the molecular species and subcellular distributi on of Alzheimer beta/A4 amyloid precursor protein (APP) in neutrophili c granulocytes purified from human peripheral blood. APP was readily d etectable in these cells. Immunochemical analysis with a panel of anti bodies revealed that this APP species lacked the transmembrane and cyt oplasmic domains previously demonstrated in cell-associated APP. Howev er, it contained a protease inhibitor domain of the Kunitz type, indic ating that neutrophil APP is a potent inhibitor of certain serine prot eases. Upon subcellular fractionation, APP was primarily localized to azurophilic granules, which are neutrophil-specific phagocytic organel les assigned to enzymatic digestion of invading microbes and dead or i njured tissue. Apparently, in the neutrophil, a nonsecretory organelle stores truncated, soluble APP, a species previously found only in blo od plasma and cerebrospinal fluid or in conditioned medium of cultured cells. Soluble APP in neutrophils may therefore have intracellular fu nctions in addition to its previously described extracellular function s. These findings also indicate that there are previously uncharacteri zed cell-specific differences in processing, trafficking, and storage of the APP molecule. Finally, the precise subcellular localization of APP to neutrophil-specific phagocytic organelles is suggestive of a ro le for APP in the nonimmunological host defense.