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Mutant Presenilin 1 Increases the Levels of Alzheimer Amyloid β‐Peptide Aβ42 in Late Compartments of the Constitutive Secretory Pathway
Author(s) -
Petanceska Suzana S.,
Seeger Mary,
Checler Frederic,
Gandy Sam
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741878.x
Subject(s) - presenilin , endoplasmic reticulum , golgi apparatus , secretory pathway , mutant , biology , microbiology and biotechnology , amyloid precursor protein , intracellular , alzheimer's disease , amyloid (mycology) , amyloid beta , biochemistry , peptide , medicine , gene , disease , botany
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 β‐peptide (Aβ42). To determine which subcellular compartments are potential source(s) of released Aβ42, we compared the levels and spatial segregation of intracellular Aβ40 and Aβ42 peptides between N2a neuroblastoma cells doubly transfected with the “Swedish” familial Alzheimer's disease‐linked amyloid precursor protein variant and either wild‐type PS1 (PS1 wt ) or familial Alzheimer's disease‐linked Δ9 mutant PS1 (PS1 Δ9 ). As expected, PS1 Δ9 ‐expressing cells had dramatically higher levels of intracellular Aβ42 than did cells expressing PS1 wt . However, the highest levels of Aβ42 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 PS1 mutants are capable of causing accumulation of Aβ42 in late compartments of the secretory pathway, generating there a readily releasable source of Aβ42. 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 PS1 “bioactivity” can control γ‐secretase‐like processing of another trans‐membrane substrate, Notch, at or near the PM.