Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

Abstract

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.

Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

“…While APP/PS1 mice utilized in our study do not have pTau accumulation, increased levels of Sirt3 and decreased activity of GSK3β suggest that CP2 treatment could also be effective in reducing Tau toxicity. Indeed, our independent study in the mouse model of AD that along with the mutant human APP and PS1 proteins also expresses mutant human Tau protein, the 3xTg-AD mice 70 , demonstrated that chronic CP2 treatment reduced pTau levels and improved LTP and energy homeostasis in symptomatic male and female mice. While this study interrogated CP2 efficacy only in female APP/ PS1 mice, treatment in 3xTg-AD mice was beneficial in males and females.…”

“…Following 24 h fixation, samples were processed using the following protocol based on the serial block-face method developed by the National Center for Microscopy and Imaging Research (La Jolla, CA; https://ncmir.ucsd. edu/sbem-protocol): (1) (14) dehydrated through ethanol series (60,70,80,95, 100, 100%) 10 min each, (15) two rinses in 100% acetone 10 min each, (16) resin 1:2, 1:1, 3:1 in acetone 0.5 h, 1 h, 2 h, overnight in 100% resin. Samples were embedded into the Durcapan hard resin (EMS, Hatfield, PA), and allowed to polymerize at a minimum of 24 h prior to trimming and mounting.…”

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

“…Further related to metabolic regulation, SIRT3, PGC1 α , TFAM, GLUT3, and GLUT4 were increased and phospho-PDH:total PDH ratio was decreased 24 h after gavage of CP2 at 25 mg/kg in APP/PS1 mice 274 . Chronic administration (2–14.5 months) improved cognition in the APP/PS1 and 3xTg mouse models of AD and decreased amyloid plaques in APP/PS1 mice after 4 months 272 , 273 , 274 , 275 .…”

Neuroimaging of Mouse Models of Alzheimer’s Disease

“…The authors suggested a deregulation of glucose uptake in 3xTg-AD mice that becomes more prominent with age. Another study also reported a significant reduction in cerebral glucose uptake in 16-month-old 3xTg-AD male and female mice compared to WT, with more prominent differences for females [ 122 ].…”