Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptideA beta 42 in late compartments of the constitutive secretory pathway

Mutations in the presenilin 1 (PS1) gene are associated with autosomal domi nant, early-onset, familial Alzheimer's disease and result in increased rel ease of the hyperaggregatable 42-amino acid form of the amyloid beta-peptid e (A beta 42). To determine which subcellular compartments are potential so urce(s) of released A beta 42, we compared the levels and spatial segregati on of intracellular A beta 40 and A beta 42 peptides between N2a neuroblast oma cells doubly transfected with the "Swedish" familial Alzheimer's diseas e-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-plas ma membrane (PM) transport vesicles. We show that PSI mutants are capable o f causing accumulation of A beta 42 in late compartments of the secretory p athway, generating there a readily releasable source of A beta 42. Our find ings indicate that PS1 "bioactivity" localizes to the vicinity of the TGN a nd/or PM and reconcile the apparent discrepancy between the preponderant co ncentration of PS1 protein in proximal compartments of the secretory pathwa y and the recent findings that PSI "bioactivity" can control gamma-secretas e-like processing of another transmembrane substrate, Notch, at or near the PM.