Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.
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.
['Stojakovic|Andrea|A|', 'Chang|Su-Youne|SY|', 'Nesbitt|Jarred|J|', 'Pichurin|Nicholas P|NP|', 'Ostroot|Mark A|MA|', 'Aikawa|Tomonori|T|', 'Kanekiyo|Takahisa|T|', 'Trushina|Eugenia|E|']
D000544:Alzheimer Disease D000818:Animals D003071:Cognition D042967:Electron Transport Complex I D004734:Energy Metabolism D019788:Fluorodeoxyglucose F18 D006624:Hippocampus D006706:Homeostasis D006801:Humans D017774:Long-Term Potentiation D008568:Memory D051379:Mice D008822:Mice, Transgenic D000084443:Morris Water Maze Test D049268:Positron-Emission Tomography D011753:Pyrones D019275:Radiopharmaceuticals D013569:Synapses D016875:tau Proteins
mitochondrial complex I fluorodeoxyglucose F18 positron-emission tomography electrophysiology 3xTg-AD transgenic mice Alzheimer’s disease human tau protein small molecule therapeutics