ArticleThe Journal of cell biology2001
The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein.
Article in The Journal of cell biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 158 citations in OpenAlex.
- APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons.Cellular and molecular neurobiology · 2023Article
- Presenilin 1 Modulates Acetylcholinesterase Trafficking and Maturation.International journal of molecular sciences · 2023Article
- Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease.Autophagy · 2022Article
- Presenilin/γ-Secretase Activity Is Located in Acidic Compartments of Live Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- CHIP modulates APP-induced autophagy-dependent pathological symptoms in Drosophila.Aging cell · 2020Article
- Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology.The Journal of cell biology · 2017Article
- G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation.Molecular neurobiology · 2015Article
- Enhanced amyloidogenic processing of amyloid precursor protein and cell death under prolonged endoplasmic reticulum stress in brain endothelial cells.Molecular neurobiology · 2015Article
- Acute ER stress regulates amyloid precursor protein processing through ubiquitin-dependent degradation.Scientific reports · 2015Article
- Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy.Neurobiology of aging · 2015Article
- The role of APP and BACE1 trafficking in APP processing and amyloid-β generation.Alzheimer's research & therapy · 2013Review
- Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-β (Aβ) production by altering trafficking of γ-secretase and amyloid precursor protein (APP).The Journal of biological chemistry · 2012Article
- Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.The EMBO journal · 2012Article
- Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Trafficking and proteolytic processing of APP.Cold Spring Harbor perspectives in medicine · 2012Review
- APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms.Cellular and molecular life sciences : CMLS · 2012Article
- Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and presenilin.Experimental brain research · 2012Review
- Lysosomal fusion dysfunction as a unifying hypothesis for Alzheimer's disease pathology.International journal of Alzheimer's disease · 2012Article
- Article
- Central angiotensin II stimulation promotes β amyloid production in Sprague Dawley rats.PloS one · 2011Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We investigated the relationship between PS1 and gamma-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 gamma-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no gamma-secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma-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 gamma-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that gamma-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 gamma-cleavage of APP-C99. In agreement, we found that intracellular gamma-secretase processing of APP-C99-KK both at the gamma40 and the gamma42 site could be restored partially after brefeldin A treatment. Our data confirm the "spatial paradox" and raise several questions regarding the PS1 is gamma-secretase hypothesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.