scholarly journals Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes

2003 ◽  
Vol 116 (16) ◽  
pp. 3339-3346 ◽  
Author(s):  
A. Kinoshita
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Early Endosomes

scholarly journals Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

2019 ◽  
Author(s):  
Tatiana Burrinha ◽  
Ricardo Gomes ◽  
Ana Paula Terrasso ◽  
Cláudia Guimas Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Early Endosomes ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

scholarly journals Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

2015 ◽  
Vol 290 (19) ◽  
pp. 12048-12057 ◽  
Author(s):  
Chao Liu ◽  
Francis Chee Kuan Tan ◽  
Zhi-Cheng Xiao ◽  
Gavin S. Dawe
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Sodium Channel ◽  
Surface Expression ◽  
Precursor Protein ◽  
Cell Surface Expression

scholarly journals The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein

2001 ◽  
Vol 154 (4) ◽  
pp. 731-740 ◽  
Author(s):  
Philippe Cupers ◽  
Mustapha Bentahir ◽  
Katleen Craessaerts ◽  
Isabelle Orlans ◽  
Hugo Vanderstichele ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Primary Cultures ◽  
Brefeldin A ◽  
Precursor Protein ◽  
Subcellular Compartment ◽  
Marker Proteins ◽  
Intermediate Compartment ◽  
The Relationship

We investigated the relationship between PS1 and γ-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent γ-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no γ-secretase processing was observed when holo-APP or APP-C99, a direct substrate for γ-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent γ-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that γ-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the γ-cleavage of APP-C99. In agreement, we found that intracellular γ-secretase processing of APP-C99-KK both at the γ40 and the γ42 site could be restored partially after brefeldin A treatment. Our data confirm the “spatial paradox” and raise several questions regarding the PS1 is γ-secretase hypothesis.

scholarly journals Amyloid Precursor Protein and Notch Intracellular Domains are Generated after Transport of their Precursors to the Cell Surface

Traffic ◽  
2006 ◽  
Vol 7 (4) ◽  
pp. 408-415 ◽  
Author(s):  
Christoph Kaether ◽  
Stephanie Schmitt ◽  
Michael Willem ◽  
Christian Haass
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Intracellular Domains

scholarly journals Calpain Activity Regulates the Cell Surface Distribution of Amyloid Precursor Protein

2002 ◽  
Vol 277 (39) ◽  
pp. 36415-36424 ◽  
Author(s):  
Paul M. Mathews ◽  
Ying Jiang ◽  
Stephen D. Schmidt ◽  
Olivera M. Grbovic ◽  
Marc Mercken ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Calpain Activity ◽  
Surface Distribution

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 The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif

2020 ◽  
Vol 77 (24) ◽  
pp. 5223-5242
Author(s):  
Simone Eggert ◽  
Tomas Gruebl ◽  
Ritu Rajender ◽  
Carsten Rupp ◽  
Bianca Sander ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Binding Protein ◽  
Precursor Protein ◽  
Early Endosomes ◽  
Β Amyloid

AbstractEndocytosis of the amyloid precursor protein (APP) is critical for generation of β-amyloid, aggregating in Alzheimer's disease. APP endocytosis depending on the intracellular NPTY motif is well investigated, whereas involvement of the YTSI (also termed BaSS) motif remains controversial. Here, we show that APP lacking the YTSI motif (ΔYTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ΔNPTY. Additionally, we show that the YTSI-binding protein, PAT1a interacts with the Rab5 activator RME-6, as shown by several independent assays. Interestingly, knockdown of RME-6 decreased APP endocytosis, whereas overexpression increased the same. Similarly, APP ΔNPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ΔYTSI internalization remained unchanged. Moreover, we could show that RME-6 mediated increase of APP endocytosis can be diminished upon knocking down PAT1a. Together, our data identify RME-6 as a novel player in APP endocytosis, involving the YTSI-binding protein PAT1a.

Cell Surface Receptor Function of Amyloid Precursor Protein That Activates Ser/Thr Kinases

Gerontology ◽  
1996 ◽  
Vol 42 (1) ◽  
pp. 2-11 ◽  
Author(s):  
Yoshitake Murayama ◽  
Shizu Takeda ◽  
Kazuyoshi Yonezawa ◽  
Ugo Giambarella ◽  
Ikuo Nishimoto ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Cell Surface Receptor ◽  
Receptor Function ◽  
Surface Receptor

scholarly journals Specific Biarsenical Labeling of Cell Surface Proteins Allows Fluorescent- and Biotin-tagging of Amyloid Precursor Protein and Prion Proteins

2009 ◽  
Vol 20 (1) ◽  
pp. 233-244 ◽  
Author(s):  
Yuzuru Taguchi ◽  
Zhen-Dan Shi ◽  
Brian Ruddy ◽  
David W. Dorward ◽  
Lois Greene ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Extracellular Proteins ◽  
Surface Proteins ◽  
Precursor Protein ◽  
Cysteine Protease Inhibitor ◽  
Steric Effects ◽  
Cell Surface Proteins ◽  
Infected Cells ◽  
Fluorescent Tagging

Fluorescent tagging is a powerful tool for imaging proteins in living cells. However, the steric effects imposed by fluorescent tags impair the behavior of many proteins. Here, we report a novel technique, Instant with DTT, EDT, And Low temperature (IDEAL)-labeling, for rapid and specific FlAsH-labeling of tetracysteine-tagged cell surface proteins by using prion protein (PrP) and amyloid precursor protein (APP) as models. In prion-infected cells, FlAsH-labeled tetracysteine-tagged PrP converted from the normal isoform (PrPsen) to the disease-associated isoform (PrPres), suggesting minimal steric effects of the tag. Pulse-chase analysis of PrP and APP by fluorescent gel imaging demonstrated the utility of IDEAL labeling in investigating protein metabolism by identifying an as-yet-unrecognized C-terminal fragment (C3) of PrPsen and by characterizing the kinetics of PrPres and APP metabolism. C3 generation and N-terminal truncation of PrPres were inhibited by the anti-prion compound E64, a cysteine protease inhibitor. Surprisingly, E64 did not inhibit the synthesis of new PrPres, providing insight into the mechanism by which E64 reduces steady-state PrPres levels in prion-infected cells. To expand the versatility of tetracysteine tagging, we created new Alexa Fluor- and biotin-conjugated tetracysteine-binding molecules that were applied to imaging PrP endocytosis and ultrastructural localization. IDEAL-labeling extends the use of biarsenical derivatives to extracellular proteins and beyond microscopic imaging.

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