Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Open accessAbstract
Defects in endosomal sorting have been implicated in Alzheimer's disease. Endosomal traffic is largely controlled by phosphatidylinositol-3-phosphate, a phosphoinositide synthesized primarily by lipid kinase Vps34. Here we show that phosphatidylinositol-3-phosphate is selectively deficient in brain tissue from humans with Alzheimer's disease and Alzheimer's disease mouse models. Silencing Vps34 causes an enlargement of neuronal endosomes, enhances the amyloidogenic processing of amyloid precursor protein in these organelles and reduces amyloid precursor protein sorting to intraluminal vesicles. This trafficking phenotype is recapitulated by silencing components of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway, including the phosphatidylinositol-3-phosphate effector Hrs and Tsg101. Amyloid precursor protein is ubiquitinated, and interfering with this process by targeted mutagenesis alters sorting of amyloid precursor protein to the intraluminal vesicles of endosomes and enhances amyloid-beta peptide generation. In addition to establishing phosphatidylinositol-3-phosphate deficiency as a contributing factor in Alzheimer's disease, these results clarify the mechanisms of amyloid precursor protein trafficking through the endosomal system in normal and pathological states.
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Cells expressing the active GTP-bound form of RAB5, RAB5 Q79L, show an enlargement of endosomes that is commonly used to facilitate discrimination between the limiting membrane and the lumen of these organelles.
“Cells expressing the active (GTP-bound) form of RAB5, RAB5 Q79L , show an enlargement of endosomes, which is commonly used to facilitate the discrimination between the limiting membrane and the lumen of these organelles. 44,45”
From NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models (2017) · cites this paper as [44]
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- Authors
- Morel, E., Chamoun, Z., Lasiecka, Z. M., Chan, R. B., Williamson, R. L., Vetanovetz, C., Dall’Armi, C., Simoes, S., Point Du Jour, K. S., McCabe, B. D., Small, S. A., & Di Paolo, G.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Small, Scott A.
- Venue
- Nature Communications
- Published
- 2013-08-02
- Volume
- 4
- Issue
- 1
- Pages
- 2250-2250
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3905799
- OpenAlex
- W1992515094
- Cited by
- 222
- References
- 55
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 10 · 2023: 12 · 2022: 19 · 2021: 15 · 2020: 23 · 2019: 26 · 2018: 14 · 2017: 19 · 2016: 21 · 2015: 19 · 2014: 17 · 2013: 2
- FWCI
- 13.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation (P50 AG008702)
- Alzheimer's Association (P50 AG008702)
- Yale University
- Broitman Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (124149)
- National Institute on Aging (R01AG025161, P50AG008702)
- National Institute of Mental Health (T32MH015174)
- National Institute of General Medical Sciences (T32GM007367)
- National Institute of Neurological Disorders and Stroke (R01NS056049, F31NS073387)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- phosphatidylinositol 3-phosphate, Vps34, amyloid precursor protein, Alzheimer's disease, endosomal sorting, ESCRT pathway, Hrs, TSG101, intraluminal vesicles, amyloid-beta production, ubiquitination, lipid kinase
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Amyloid, Animals, Brain, HeLa Cells, Humans, Molecular Sequence Data, Neurons, Protein Processing, Post-Translational, Endosomes, Subcellular Fractions, Amyloid beta-Protein Precursor, Phosphatidylinositol Phosphates, Gene Silencing, Protein Transport, Mutant Proteins, Mice, Ubiquitination, Endosomal Sorting Complexes Required for Transport, HEK293 Cells, Class III Phosphatidylinositol 3-Kinases
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