PRODUCTION OF THE ALZHEIMER AMYLOID-BETA PROTEIN BY NORMAL PROTEOLYTIC PROCESSING

The 4-kilodalton (39 to 43 amino acids) amyloid beta protein (betaAP), which is deposited as amyloid in the brains of patients with Alzheimer's disease, is derived from a large protein, the amyloid beta protein precursor (betaAPP). Human mononuclear leukemic (K562) cells expressing a betaAP-bearing, carboxyl-terminal betaAPP derivative released significant amounts of a soluble 4-kilodalton betaAPP derivative essentially identical to the betaAP deposited in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing full-length betaAPP and M17 cells expressing only endogenous betaAPP also released soluble 4-kilodalton betaAP, and a similar, if not identical, fragment was readily detected in cerebrospinal fluid from individuals with Alzheimer's disease and normal individuals. Thus cells normally produce and release soluble 4-kilodalton betaAP that is essentially identical to the 4-kilodalton betaAP deposited as insoluble amyloid fibrils in Alzheimer's disease.