SECRETORY CLEAVAGE OF BETA-AMYLOID PRECURSOR PROTEIN IN THE CEREBRAL WHITE-MATTER PRODUCES AMYLOIDOGENIC CARBOXYL-TERMINAL FRAGMENTS

To elucidate the metabolic process generating amyloid-beta protein (A beta) from beta-amyloid precursor protein (APP) in human brain, we par tially purified secretory forms and carboxyl-terminal fragments (CTFs) of APP from the white matter of a Down's syndrome brain. We obtained secretory forms of APP which lack the entire A beta sequence and CTFs which contain the full-length A beta from the cerebral white matter. S ome A beta-lacking secretory APP isoforms in the white matter were der ived from APP695. These results suggest that amyloidogenic CTFs can be produced by secretory cleavage of APP which is anterogradely transpor ted through the axon in human brain.