A Role for Presenilin 1 in Regulating the Delivery of Amyloid Precursor Protein to the Cell Surface

2002 ◽  
Vol 11 (1) ◽  
pp. 64-82 ◽  
Author(s):  
Jae Yoon Leem ◽  
Carlos A. Saura ◽  
Claus Pietrzik ◽  
John Christianson ◽  
Christian Wanamaker ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals Presenilin-1 Regulates Intracellular Trafficking and Cell Surface Delivery of β-Amyloid Precursor Protein

2002 ◽  
Vol 278 (5) ◽  
pp. 3446-3454 ◽  
Author(s):  
Dongming Cai ◽  
Jae Yoon Leem ◽  
Jeffrey P. Greenfield ◽  
Pei Wang ◽  
Benny S. Kim ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Intracellular Trafficking ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Β Amyloid

scholarly journals The Role of Presenilin-1 in the γ-Secretase Cleavage of the Amyloid Precursor Protein of Alzheimer's Disease

2000 ◽  
Vol 275 (3) ◽  
pp. 1525-1528 ◽  
Author(s):  
Jean-Noël Octave ◽  
Rachid Essalmani ◽  
Bernadette Tasiaux ◽  
Jean Menager ◽  
Christian Czech ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals P3-385: Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1(BACE1)

2006 ◽  
Vol 2 ◽  
pp. S489-S489
Author(s):  
Akira Kuzuya ◽  
Kengo Uemura ◽  
Ayae Kinoshita ◽  
Shun Shimohama
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals Notch1 Competes with the Amyloid Precursor Protein for γ-Secretase and Down-regulates Presenilin-1 Gene Expression

2003 ◽  
Vol 278 (48) ◽  
pp. 47370-47375 ◽  
Author(s):  
Alberto Lleó ◽  
Oksana Berezovska ◽  
Pavan Ramdya ◽  
Hiroaki Fukumoto ◽  
Susan Raju ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

THE PROCESSING OF THE AMYLOID-PRECURSOR-PROTEIN (APP) IN PRESENILIN-1 DEFICIENT NEURONS

2010 ◽  
Author(s):  
PAUL SAFTIG ◽  
DIETER HARTMANN ◽  
WIM ANNAERT ◽  
KATHLEEN CRAESSAERTS ◽  
FRED VAN LEUVEN ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals Presenilin 1 Controls γ-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons

1999 ◽  
Vol 147 (2) ◽  
pp. 277-294 ◽  
Author(s):  
Wim G. Annaert ◽  
Lyne Levesque ◽  
Kathleen Craessaerts ◽  
Inge Dierinck ◽  
Greet Snellings ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Subcellular Fractionation ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Carboxy Terminal ◽  
Endocytic Pathways

Mutations of presenilin 1 (PS1) causing Alzheimer's disease selectively increase the secretion of the amyloidogenic βA4(1-42), whereas knocking out the gene results in decreased production of both βA4(1-40) and (1-42) amyloid peptides (De Strooper et al. 1998). Therefore, PS1 function is closely linked to the γ-secretase processing of the amyloid precursor protein (APP). Given the ongoing controversy on the subcellular localization of PS1, it remains unclear at what level of the secretory and endocytic pathways PS1 exerts its activity on APP and on the APP carboxy-terminal fragments that are the direct substrates for γ-secretase. Therefore, we have reinvestigated the subcellular localization of endogenously expressed PS1 in neurons in vitro and in vivo using confocal microscopy and fine-tuned subcellular fractionation. We show that uncleaved PS1 holoprotein is recovered in the nuclear envelope fraction, whereas the cleaved PS fragments are found mainly in post-ER membranes including the intermediate compartment (IC). PS1 is concentrated in discrete sec23p- and p58/ERGIC-53–positive patches, suggesting its localization in subdomains involved in ER export. PS1 is not found to significant amounts beyond the cis-Golgi. Surprisingly, we found that APP carboxy-terminal fragments also coenrich in the pre-Golgi membrane fractions, consistent with the idea that these fragments are the real substrates for γ-secretase. Functional evidence that PS1 exerts its effects on γ-secretase processing of APP in the ER/IC was obtained using a series of APP trafficking mutants. These mutants were investigated in hippocampal neurons derived from transgenic mice expressing PS1wt or PS1 containing clinical mutations (PS1M146L and PS1L286V) at physiologically relevant levels. We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of βA4(1-42) relative to βA4(1-40), indicating that both mutations operate independently. Overall, our data clearly establish that PS1 controls γ42-secretase activity in pre-Golgi compartments. We discuss models that reconcile this conclusion with the effects of PS1 deficiency on the generation of βA4(1-40) peptide in the late biosynthetic and endocytic pathways.

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