Partial inhibition of mitochondrial complex I ameliorates Alzheimer's disease pathology and cognition in APP/PS1 female mice.
Alzheimer Disease
/ drug therapy
Animals
Brain
/ drug effects
Cognition
/ drug effects
Disease Models, Animal
Drug Evaluation, Preclinical
Electron Transport Complex I
/ antagonists & inhibitors
Female
Mice, Inbred C57BL
Mice, Transgenic
Neuroprotection
Proof of Concept Study
Pyrones
/ pharmacology
Signal Transduction
/ drug effects
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
08 01 2021
08 01 2021
Historique:
received:
19
06
2020
accepted:
08
12
2020
entrez:
9
1
2021
pubmed:
10
1
2021
medline:
3
7
2021
Statut:
epublish
Résumé
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET,
Identifiants
pubmed: 33420340
doi: 10.1038/s42003-020-01584-y
pii: 10.1038/s42003-020-01584-y
pmc: PMC7794523
doi:
Substances chimiques
CP2 compound
0
Pyrones
0
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
61Subventions
Organisme : NINDS NIH HHS
ID : R01 NS088260
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG013925
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107265
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG062413
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG055549
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NINDS NIH HHS
ID : UH3 NS113776
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS112381
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062135
Pays : United States
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