Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.
Alzheimer Disease
/ metabolism
Animals
Cognition
/ drug effects
Electron Transport Complex I
/ antagonists & inhibitors
Energy Metabolism
/ drug effects
Fluorodeoxyglucose F18
Hippocampus
/ drug effects
Homeostasis
/ drug effects
Humans
Long-Term Potentiation
/ drug effects
Memory
/ drug effects
Mice
Mice, Transgenic
Morris Water Maze Test
Positron-Emission Tomography
Pyrones
/ pharmacology
Radiopharmaceuticals
Synapses
/ drug effects
tau Proteins
/ drug effects
3xTg-AD transgenic mice
Alzheimer’s disease
electrophysiology
fluorodeoxyglucose F18 positron-emission tomography
human tau protein
mitochondrial complex I
small molecule therapeutics
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2021
2021
Historique:
pubmed:
9
12
2020
medline:
28
9
2021
entrez:
8
12
2020
Statut:
ppublish
Résumé
Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer's disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.
Sections du résumé
BACKGROUND
Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer's disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown.
OBJECTIVE
To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms.
METHODS
CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting.
RESULTS
Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).
CONCLUSION
CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.
Identifiants
pubmed: 33285637
pii: JAD201015
doi: 10.3233/JAD-201015
pmc: PMC7902954
doi:
Substances chimiques
CP2 compound
0
Pyrones
0
Radiopharmaceuticals
0
tau Proteins
0
Fluorodeoxyglucose F18
0Z5B2CJX4D
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-353Subventions
Organisme : NINDS NIH HHS
ID : R01 NS107265
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG055549
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062135
Pays : United States
Organisme : NINDS NIH HHS
ID : UH3 NS113776
Pays : United States
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