Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.
Aged
Aged, 80 and over
Alzheimer Disease
/ metabolism
Amyloid Precursor Protein Secretases
/ antagonists & inhibitors
Amyloid beta-Protein Precursor
/ genetics
Animals
Aspartic Acid Endopeptidases
/ antagonists & inhibitors
Autopsy
Brain
/ pathology
Cell Line
Female
Humans
Membrane Potential, Mitochondrial
Mice
Mitochondria
/ metabolism
Mitophagy
/ genetics
Peptide Fragments
/ genetics
Reactive Oxygen Species
/ metabolism
APP-CTFs
Alzheimer’s disease
Amyloid beta
Amyloid precursor protein
C83
C99
Mitochondria
Mitophagy
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
09
06
2020
accepted:
01
10
2020
revised:
03
09
2020
pubmed:
21
10
2020
medline:
26
10
2021
entrez:
20
10
2020
Statut:
ppublish
Résumé
Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer's disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.
Identifiants
pubmed: 33079262
doi: 10.1007/s00401-020-02234-7
pii: 10.1007/s00401-020-02234-7
pmc: PMC7785558
doi:
Substances chimiques
APP protein, human
0
Amyloid beta-Protein Precursor
0
Peptide Fragments
0
Reactive Oxygen Species
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
BACE1 protein, human
EC 3.4.23.46
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
39-65Références
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