Abstract
Our early study indicates that intracellular Abeta1-42 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 Abeta1-42 also leads to the accumulation of newly synthesized intracellular Abeta. Here we describe that newly synthesized Abeta, especially Abetan-42, is generated from metabolically labeled APP and accumulates in the insoluble fraction of cell lysates after Abeta1-42 treatment. These results suggest that intracellular Abeta may derive from a solid phase, intracellular pathway. In contrast to the pathway that primarily produces secreted Abeta1-40, the solid-phase intracellular pathway preferentially produces Abetan-42 with ragged amino termini. Biochemical studies and amino acid sequencing analyses indicate that these intracellular Abeta also share the same types of Abeta 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.
Highlights
The major protein component of amyloid deposits associated with Alzheimer’s disease (AD)1 is a 39 – 42-amino acid, selfassembling peptide known as the amyloid A peptide
We examined whether the presence of intracellular A affects the catabolism of amyloid precursor protein (APP) and A in APP-overexpressing human embryonic kidney 293 cells since both nonamyloidogenic and amyloidogenic APP-processing pathways have been demonstrated in this cell line
Because the amyloidogenic fragments of APP accumulate in the nonionic detergent-insoluble fraction of cells treated with A1– 42 [20], we investigated whether some of these fragments are converted to 4-kDa A
Summary
The major protein component of amyloid deposits associated with Alzheimer’s disease (AD) is a 39 – 42-amino acid, selfassembling peptide known as the amyloid A peptide. Recent evidence indicates that the familial AD amino acid substitutions within the APP transmembrane domain and presenilin favor the production of A1– 42 form of A, which is preferentially localized within diffuse plaques and senile plaques in AD brain This suggests that A1– 42 is more closely associated with AD pathogenesis than shorter A isoforms [9, 10]. The APP amyloidogenic fragments appear to undergo such a conformation change, since they display an epitope that is associated with A aggregates [20] This suggests that they may have the same shape as aggregated A and are capable of adding on to the fibril lattice established by the internalized exogenous A1– 42. To complete the prion-like cycle, the APP amyloidogenic fragments would need to be further proteolytically processed to A
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