Contribution of the Endosomal-Lysosomal and Proteasomal Systems in Amyloid-β Precursor Protein Derived Fragments Processing

Evrard, Caroline; Kienlen‐Campard, Pascal; Coevoet, Mathilde; Opsomer, Reinier-Jacques; Tasiaux, Bernadette; Melnyk, Patricia; Octave, Jean‐Noël; Buée, Luc; Sergeant, Nicolas; Vingtdeux, Valérie

doi:10.3389/fncel.2018.00435

Cited by 29 publications

(16 citation statements)

References 50 publications

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“…Our study shows that the proteasome is a prominent scavenging system for C99 under control conditions, in agreement with previous data also obtained in a HEK model of C99 overexpression [47], and in primary neurons from transgenic mice overexpressing C99 [48].…”

Section: The Fate Of C99 and C83supporting

confidence: 93%

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

García-González

Paumier

Louis

et al. 2020

Preprint

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We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

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Section: The Fate Of C99 and C83supporting

confidence: 93%

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

García-González

Paumier

Louis

et al. 2020

Preprint

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show abstract

“…Unprocessed APP is internalized into the endosomal compartment, which contains β-secretase enzymes that cleave APP to produce sAPPβ and Β-secretase derived C-terminal fragment of APP (CTFβ). Next, γ-secretase cleaves CTFβ to produce CTFγ and Aβ [ 12 , 13 ]. Recent research identifying new secretases such as δ-secretase, η-secretase, and meprin-β have added to the intricacy of APP processing [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Alix and Syntenin-1 direct amyloid precursor protein trafficking into extracellular vesicles

Cone

Hurwitz

Lee

et al. 2020

BMC Mol and Cell Biol

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Background: Endosomal trafficking and amyloidogenic cleavage of amyloid precursor protein (APP) is believed to play a role in the neurodegeneration observed in Alzheimer's disease (AD). Recent evidence has suggested that packaging and secretion of APP and its amyloidogenic cleaved products into small extracellular vesicles (EVs) may facilitate uptake of these neurotoxic factors during disease progression. However, the molecular mechanisms underlying trafficking of APP into EVs are poorly understood. Results: In this study, the mechanism and impact of APP trafficking into extracellular vesicles (EVs) were assessed by a series of inducible gene knockdowns. We demonstrate that vesicle-associated proteins Alix and Syntenin-1 are essential for proper subcellular localization and efficient EV secretion of APP via an endosomal sorting complexes required for transport (ESCRT)-independent pathway. The neurotoxic C-terminal fragment (CTFβ) of APP is similarly secreted in association with small vesicles. These mechanisms are conserved in terminally differentiated neuron-like cells. Furthermore, knockdown of Alix and Syntenin-1 alters the subcellular localization of APP, sequestering the precursor protein to endoplasmic reticulum and endolysosomal compartments, respectively. Finally, transfer of small EVs containing mutant APP confers an increase in reactive oxygen species production and neurotoxicity to human induced pluripotent stem cell-derived cortical neurons and naïve primary neurons, an effect that is ameliorated by Alix and Syntenin-1 depletion. Conclusions: Altogether these findings elucidate a novel mechanism for understanding the intracellular trafficking of APP and CTFβ into secreted extracellular vesicles, and the resultant potential impact on neurotoxicity in the context of Alzheimer's disease amyloidopathy.

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“…The levels of APP-CTFs in the human AD brain have not been investigated thoroughly, probably because APP intracellular fragments are quickly processed by γ-secretase, and/or degraded through autophagy and the endosomal-lysosomal pathway [8,18,23]. Moreover, the specificity of the APP-CTF bands in western blots has been recurrently questioned [26].…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer’s disease

et al. 2020

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Background: The amyloid precursor protein (APP) is a transmembrane glycoprotein that undergoes alternative proteolytic processing. Its processing through the amyloidogenic pathway originates a large sAPPβ ectodomain fragment and the β-amyloid peptide, while non-amyloidogenic processing generates sAPPα and shorter nonfibrillar fragments. Hence, measuring sAPPα and sAPPβ has been proposed as a means to identify imbalances between the amyloidogenic/non-amyloidogenic pathways in the brain of Alzheimer's disease (AD) patients. However, to date, no consistent changes in these proteolytic fragments have been identified in either the brain or cerebrospinal fluid of AD individuals. Methods: In frontal cortex homogenates from AD patients (n = 7) and non-demented controls (NDC; n = 7), the expression of total APP mRNA and that of the APP isoforms generated by alternative splicing, APP695 and APP containing the Kunitz protease inhibitor (KPI), was analyzed by qRT-PCR using TaqMan and SYBR Green probes. The balance between the amyloidogenic/non-amyloidogenic pathways was examined in western blots estimating the sAPPα and sAPPβ fragments and their membrane-tethered C-terminal fragments CTFα and CTFβ. CHO-PS70 cells, stably over-expressing wild-type human APP, served to evaluate whether Aβ42 peptide treatment results in altered APP glycosylation. We determined the glycosylation pattern of sAPPα and sAPPβ in brain extracts and CHO-PS70 culture media by lectin-binding assays. Results: In the cortex of AD patients, we detected an increase in total APP mRNA relative to the controls, due to an increase in both the APP695 and APP-KPI variants. However, the sAPPα or sAPPβ protein levels remained unchanged, as did those of CTFα and CTFβ. We studied the glycosylation of the brain sAPPα and sAPPβ using lectins and pan-specific antibodies to discriminate between the fragments originated from neuronal APP695 and glial/KPI variants. Lectin binding identified differences in the glycosylation of sAPPβ species derived from the APP695 and APP-KPI variants, probably reflecting their distinct cellular origin. Moreover, the lectin-binding pattern differed in the sAPPα and sAPPβ originated from all the variants. Finally, when the lectin-binding pattern was compared between AD and NDC groups, significant differences were evident in sAPPα glycosylation. Lectin binding of the soluble sAPPα and sAPPβ from CHO-PS70 cells were also altered in cells treated with the Aβ peptide.

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Contribution of the Endosomal-Lysosomal and Proteasomal Systems in Amyloid-β Precursor Protein Derived Fragments Processing

Cited by 29 publications

References 50 publications

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

Alix and Syntenin-1 direct amyloid precursor protein trafficking into extracellular vesicles

Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer’s disease

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