Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 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 Abeta42, 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 PS1 (PS1(wt)) or familial Alzheimer's disease-linked delta9 mutant PS1 (PS1delta9). As expected, PS1delta9-expressing cells had dramatically higher levels of intracellular Abeta42 than did cells expressing PS1wt. 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 PS1 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 PS1 "bioactivity" can control gamma-secretase-like processing of another transmembrane substrate, Notch, at or near the PM.
Petanceska
S S
SS
New York University at Nathan Kline Institute, Orangeburg 10962, USA.
Seeger
M
M
Checler
F
F
Gandy
S
S
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1; D013347:Subcellular Fractions / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)