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Cited by 219Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology

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Lauritzen, Inger, Pardossi-Piquard, Raphaëlle, Bourgeois, Alexandre, Pagnotta, Sophie, Biferi, Maria-Grazia, Barkats, Martine, Lacor, Pascale, Klein, William +2 more·2016·Acta Neuropathologica
DOI 10.1007/s00401-016-1577-6PMC PMC4947121
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Abstract

Endosomal-autophagic-lysosomal (EAL) dysfunction is an early and prominent neuropathological feature of Alzheimers’s disease, yet the exact molecular mechanisms contributing to this pathology remain undefined. By combined biochemical, immunohistochemical and ultrastructural approaches, we demonstrate a link between EAL pathology and the intraneuronal accumulation of the β-secretase-derived βAPP fragment (C99) in two in vivo models, 3xTgAD mice and adeno-associated viral-mediated C99-infected mice. We present a pathological loop in which the accumulation of C99 is both the effect and causality of impaired lysosomal-autophagic function. The deleterious effect of C99 was found to be linked to its aggregation within EAL-vesicle membranes leading to disrupted lysosomal proteolysis and autophagic impairment. This effect was Aβ independent and was even exacerbated when γ-secretase was pharmacologically inhibited. No effect was observed in inhibitor-treated wild-type animals suggesting that lysosomal dysfunction was indeed directly linked to C99 accumulation. In some brain areas, strong C99 expression also led to inflammatory responses and synaptic dysfunction. Taken together, this work demonstrates a toxic effect of C99 which could underlie some of the early-stage anatomical hallmarks of Alzheimer’s disease pathology. Our work also proposes molecular mechanisms likely explaining some of the unfavorable side-effects associated with γ-secretase inhibitor-directed therapies.

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  • L685,458 boosts APP-βCTF levels by inhibiting its cleavage.

    “which boosts APP-␤CTF levels by inhibiting its cleavage (Fig. 5 A, B) (Jiang et al., 2010;Lauritzen et al., 2016;Hung and Livesey, 2018).”

    From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Lauritzen et al., 2016

    The Results section (Fig. 5a; page unavailable) reports that the γ-secretase inhibitor ELND006 increased C99, an APP-βCTF. This supports the general effect of inhibiting its cleavage, but the paper does not identify or test L685,458, so it does not establish the claim for that specific compound. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • There is evidence that alternative APP-derived fragments as well as APP itself play important roles in the modulation of immune cell activation, protein clearance, and lipid homeostasis.

    “Indeed, there is evidence that alternative APP-derived fragments as well as APP itself play important roles in the modulation of immune cell activation [160], protein clearance [161], and lipid homeostasis [162].”

    From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [161]

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References 64 · Cited by 219

Research works printed but not linked: 58

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Authors
Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M.-G., Barkats, M., Lacor, P., Klein, W., Bauer, C., & Checler, F.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Université Nice Sophia Antipolis (FR)
  • Institut de Myologie (FR)
  • Northwestern University (US)
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2016-04-30
Volume
132
Issue
2
Pages
257-276
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-016-1577-6
PMC
PMC4947121
OpenAlex
W2344407798
Cited by
219
References
64
Citations by year
2026: 12 · 2025: 20 · 2024: 22 · 2023: 19 · 2022: 27 · 2021: 32 · 2020: 29 · 2019: 22 · 2018: 16 · 2017: 16 · 2016: 4
FWCI
15.57
Type
journal article
Language
en
Update notices
correction (2023-08-04)
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Labex DistALZ
  • Conseil départemental Alpes-Côte d'Azur
  • University Hospital Federation OncoAge
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, lysosomal proteolysis, autophagy dysfunction, gamma-secretase inhibition, neuroinflammation, synaptic dysfunction, 3xTg-AD mice
MeSH terms
Alzheimer Disease, Animals, Autophagy, Brain, Disease Models, Animal, Lysosomes, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Endosomes, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases

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