Intracellular accumulation of insoluble, newly synthesized Aβn-42 in amyloid precursor protein-transfected cells that have been treated with Aβ1-42

Our early study indicates that intracellular A beta 1-42 aggregates are resistant to degradation and accumulate as an insoluble residue in lysosomes, where they alter the normal catabolism of amyloid precursor protein (APP) to cause the accumulation of insoluble APP and amyloidogenic fragments. In this study, we examined whether the addition of exogenous A beta 1-42 also leads to the accumulation of newly synthesized intracellular A beta. Here we describe that newly synthesized A beta, especially A beta n-42, is generated from metabolically labeled APP and accumulates in the insoluble fraction of cell lysates after A beta 1-42 treatment. These results suggest that intracellular A beta may derive from a solid phase, intracellular pathway. In contrast to the pathway that primarily produces secreted A beta 1-40, the solid-phase intracellular pathway preferentially produces A beta n-42 with ragged amino termini. Biochemical studies and amino acid sequencing analyses indicate that these intracellular A beta also share the same types of A beta structures that accumulate in the brain of Alzheimer's disease patients, suggesting that a significant fraction of the amyloid deposits in Alzheimer's disease may arise by this solid-phase pathway.