Mutant presenilin 1 increases the levels of Alzheimer amyloid β-peptide Aβ42 in late compartments of the constitutive secretory pathway

Mutations in the presenilin 1 (PS1) gene are associated with autosomal dominant, early-onset, familial Alzheimer's disease and result in increased release of the hyperaggregatable 42-amino acid form of the amyloid beta-peptide (A beta 42). To determine which subcellular compartments are potential source(s) of released A beta 42, we compared the levels and spatial segregation of intracellular A beta 40 and A beta 42 peptides between N2a neuroblastoma cells doubly transfected with the "Swedish" familial Alzheimer's disease-linked amyloid precursor protein variant and either wild-type PSI (PS1(wt)) or familial Alzheimer's disease-linked Delta 9 mutant PS1 (PS1(Delta 9)). As expected, PS1(Delta 9)-expressing cells had dramatically higher levels of intracellular A beta 42 than did cells expressing PS1(wt). However, the highest levels of A beta 42 colocalized not with endoplasmic reticulum or Golgi markers but with rab8, a marker for trans-Golgi network (TGN)-to-plasma membrane (PM) transport vesicles. We show that PSI mutants are capable of causing accumulation of A beta 42 in late compartments of the secretory pathway, generating there a readily releasable source of A beta 42. Our findings indicate that PS1 "bioactivity" localizes to the vicinity of the TGN and/or PM and reconcile the apparent discrepancy between the preponderant concentration of PS1 protein in proximal compartments of the secretory pathway and the recent findings that PSI "bioactivity" can control gamma-secretase-like processing of another transmembrane substrate, Notch, at or near the PM.