scholarly journals Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein

2005 ◽  
Vol 25 (11) ◽  
pp. 3009-3017 ◽  
Author(s):  
O. Berezovska
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature ◽  
1991 ◽  
Vol 349 (6311) ◽  
pp. 704-706 ◽  
Author(s):  
Alison Goate ◽  
Marie-Christine Chartier-Harlin ◽  
Mike Mullan ◽  
Jeremy Brown ◽  
Fiona Crawford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Missense Mutation ◽  
Protein Gene ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Gene ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease

scholarly journals Syntaxin 5 interacts with presenilin holoproteins, but not with their N- or C-terminal fragments, and affects β-amyloid peptide production

2004 ◽  
Vol 381 (3) ◽  
pp. 619-628 ◽  
Author(s):  
Kei SUGA ◽  
Takami TOMIYAMA ◽  
Hiroshi MORI ◽  
Kimio AKAGAWA
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Full Length ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Familial Alzheimer’S Disease ◽  
Aβ Amyloid ◽  
Β Amyloid ◽  
Familial Alzheimer's Disease

Mutations in presenilins 1 and 2 (PS1 and PS2) account for the majority of cases of early-onset familial Alzheimer's disease. However, the trafficking and interaction of PSs with other proteins in the early secretory pathways are poorly understood. Using co-immunoprecipitation, we found that PS bound to Syx5 (syntaxin 5), which is a target-soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor involved in endoplasmic reticulum (ER)–Golgi vesicular transport in vivo. Syx5 interacted only with the full-length PS holoproteins and not with the naturally occurring N- or C-terminal fragments. The PS holoproteins co-immunoprecipitated with the mutant Syx5, which localized to the ER and Golgi compartments, despite the substitution of the transmembrane region with that of syntaxin 1A. In contrast, the transmembrane deletion mutant that localized to the cytosol, but not to the ER or Golgi compartments, did not co-immunoprecipitate the PS holoproteins. The PS1 variant linked to familial Alzheimer's disease (PS1ΔE9), lacking the region that contains the endoproteolytic cleavage site in the cytoplasmic loop, showed markedly decreased binding to Syx5. Immunofluorescence and sucrose-density-gradient fractionation analyses showed that the full-length PS holoproteins co-localized with Syx5 to the ER and cis-Golgi compartments. Furthermore, Syx5 overexpression resulted in the accumulation of PS holoproteins and the β-amyloid precursor protein, and reduced the secretion of the Aβ (amyloid β) peptide in COS-7 cells. In summary, these results indicate that Syx5 binds to full-length PSs and affects the processing and trafficking of β-amyloid precursor protein in the early secretory compartments.

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