ArticleTranslational neurodegeneration2019
Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models.
Article in Translational neurodegeneration, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 43 citations in OpenAlex.
- Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer's disease.The EMBO journal · 2026Article
- Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.Cell communication and signaling : CCS · 2026Article
- ADAM10-Mediated Proteolytic Remodelling of Signalling and Adhesion Proteins on Brain Cell-Derived Small Extracellular Vesicles.Journal of extracellular biology · 2026Article
- The Multifaceted Role of Extracellular Vesicles in Alzheimer's Disease.Journal of neurochemistry · 2025Review
- Presenilins as hub proteins controlling the endocytic and autophagic pathways and small extracellular vesicle secretion.Journal of extracellular vesicles · 2025Article
- Suppression of MT5-MMP Reveals Early Modulation of Alzheimer's Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice.Biomolecules · 2024Article
- Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases.Nature reviews. Molecular cell biology · 2024Review
- Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.Acta neuropathologica · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aβ production.Cellular and molecular life sciences : CMLS · 2023Article
- The Potential Roles of Exosomes Carrying APP and Tau Cleavage Products in Alzheimer's Disease.Journal of clinical medicine · 2023Review
- Extracellular vesicles in the study of Alzheimer's and Parkinson's diseases: Methodologies applied from cells to biofluids.Journal of neurochemistry · 2022Review
- A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.Cell reports. Medicine · 2022Article
- The amyloid precursor protein: a converging point in Alzheimer's disease.Molecular neurobiology · 2022Review
- Parkin as a Molecular Bridge Linking Alzheimer's and Parkinson's Diseases?Biomolecules · 2022Review
- MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease.Journal of neuroinflammation · 2022Article
- Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.Cell death discovery · 2022Article
- Mitochondrial Targeting of Amyloid-β Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-β.Journal of Alzheimer's disease : JAD · 2022Article
- Implications of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology.Disease models & mechanisms · 2021Article
- TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition.Life science alliance · 2021Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundWe recently demonstrated an endolysosomal accumulation of the β-secretase-derived APP C-terminal fragment (CTF) C99 in brains of Alzheimer disease (AD) mouse models. Moreover, we showed that the treatment with the γ-secretase inhibitor (D6) led to further increased endolysosomal APP-CTF levels, but also revealed extracellular APP-CTF-associated immunostaining. We here hypothesized that this latter staining could reflect extracellular vesicle (EV)-associated APP-CTFs and aimed to characterize these γ-secretase inhibitor-induced APP-CTFs.
methodsEVs were purified from cell media or mouse brains from vehicle- or D6-treated C99 or APP
resultsPurified EVs from both AD cell or mouse models were enriched in APP-CTFs as compared to EVs from control cells/brains. Surprisingly, EVs from D6-treated cells not only displayed increased C99 and C99-derived C83 levels but also higher molecular weight (HMW) APP-CTF-immunoreactivities that were hardly detectable in whole cell extracts. Accordingly, the intracellular levels of HMW APP-CTFs were amplified by the exosomal inhibitor GW4869. By combined pharmacological, immunological and genetic approaches, we established that these HMW APP-CTFs correspond to oligomeric APP-CTFs composed of C99 and/or C83. Immunocytochemical analysis showed that monomers were localized mainly to the
conclusionsThis is the first study to demonstrate the presence of oligomeric APP-CTFs in AD mouse models, the levels of which are selectively enriched in endolysosomal compartments including exosomes and amplified by γ-secretase inhibition. Future studies should evaluate the putative contribution of these exosome-associated APP-CTFs in AD onset, progression and spreading.
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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.