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Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, Jin LW, Prasain K, Nguyen TD, Yamazaki Y, Kanekiyo T, Bu G, Gateno B, Chang KO, Nath KA, Nemutlu E, Dzeja P, Pang YP, Hua DH, Trushina E - EBioMedicine (2015)

Bottom Line: Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress.Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice.Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.

ABSTRACT

Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

No MeSH data available.


Related in: MedlinePlus

Chronic CP2 treatment averts the development of behavior and memory phenotype in FAD mice.(A) CP2 structure. (B) P and F1 animals treated with 25 mg/kg/day CP2 produced F1 progeny that were treated with CP2 till 14 months of age. F2 pups were used for axonal trafficking experiments. (C, D) CP2-treated PS1 (C, light gray; n = 5) and APP (D, light gray, n = 5) mice maintained body weight similar to NTG untreated mice (black, n = 10), while untreated PS1 (C, dark gray, n = 10) and APP (D, dark gray, n = 10) mice accumulated weight with age. *P < 0.05. (E) CP2-treated APP mice (red, n = 5) did not display muscle weakness or altered prehensile reflex in hanging bar test compared to untreated APP animals (gray, n = 10). Black — untreated NTG, n = 10. *P < 0.05. (F) Time on a rod rotating at 20 rpm. CP2-treated PS1 (orange, n = 5) and APP (dark blue, n = 5); untreated APP (light blue, n = 10), PS1 (gray, n = 10), and NTG mice (black, n = 10). Mice were 56 weeks old. *P < 0.05. (G, H) NOR test demonstrates that CP2-treated APP (G, light orange bars: training session; red bars: NOR, n = 5) and PS1 (H, light blue bars: training session; dark blue bars: NOR, n = 5) mice maintained the ability to recognize a familiar object similar to NTG animals (n = 10) while their untreated counterparts (n = 10 for APP and n = 10 for PS1) lost that ability with age. *P < 0.05. See also Figs. S1 and S2.
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f0005: Chronic CP2 treatment averts the development of behavior and memory phenotype in FAD mice.(A) CP2 structure. (B) P and F1 animals treated with 25 mg/kg/day CP2 produced F1 progeny that were treated with CP2 till 14 months of age. F2 pups were used for axonal trafficking experiments. (C, D) CP2-treated PS1 (C, light gray; n = 5) and APP (D, light gray, n = 5) mice maintained body weight similar to NTG untreated mice (black, n = 10), while untreated PS1 (C, dark gray, n = 10) and APP (D, dark gray, n = 10) mice accumulated weight with age. *P < 0.05. (E) CP2-treated APP mice (red, n = 5) did not display muscle weakness or altered prehensile reflex in hanging bar test compared to untreated APP animals (gray, n = 10). Black — untreated NTG, n = 10. *P < 0.05. (F) Time on a rod rotating at 20 rpm. CP2-treated PS1 (orange, n = 5) and APP (dark blue, n = 5); untreated APP (light blue, n = 10), PS1 (gray, n = 10), and NTG mice (black, n = 10). Mice were 56 weeks old. *P < 0.05. (G, H) NOR test demonstrates that CP2-treated APP (G, light orange bars: training session; red bars: NOR, n = 5) and PS1 (H, light blue bars: training session; dark blue bars: NOR, n = 5) mice maintained the ability to recognize a familiar object similar to NTG animals (n = 10) while their untreated counterparts (n = 10 for APP and n = 10 for PS1) lost that ability with age. *P < 0.05. See also Figs. S1 and S2.

Mentions: We have previously identified small molecule tricyclic pyrone CP2 (Fig. 1A) that protects cells against Aβ toxicity, and reduces brain Aβ in 5 × FAD mice (Hong et al., 2009; Maezawa et al., 2006). To examine the molecular mechanism, we first tested whether CP2 penetrates the blood–brain barrier (BBB). C14-Labeled CP2 was injected intraperitoneally to wild type (WT) mice, and levels were measured in the brain tissue 30 min post-injection (Fig. S1A, B). Results suggest that CP2 rapidly accumulates in the brain. Additional pharmacokinetics studies conducted in plasma of WT mice after intravenous or oral administration demonstrated that CP2 bioavailability is 43% (Fig. S1C, D).


Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, Jin LW, Prasain K, Nguyen TD, Yamazaki Y, Kanekiyo T, Bu G, Gateno B, Chang KO, Nath KA, Nemutlu E, Dzeja P, Pang YP, Hua DH, Trushina E - EBioMedicine (2015)

Chronic CP2 treatment averts the development of behavior and memory phenotype in FAD mice.(A) CP2 structure. (B) P and F1 animals treated with 25 mg/kg/day CP2 produced F1 progeny that were treated with CP2 till 14 months of age. F2 pups were used for axonal trafficking experiments. (C, D) CP2-treated PS1 (C, light gray; n = 5) and APP (D, light gray, n = 5) mice maintained body weight similar to NTG untreated mice (black, n = 10), while untreated PS1 (C, dark gray, n = 10) and APP (D, dark gray, n = 10) mice accumulated weight with age. *P < 0.05. (E) CP2-treated APP mice (red, n = 5) did not display muscle weakness or altered prehensile reflex in hanging bar test compared to untreated APP animals (gray, n = 10). Black — untreated NTG, n = 10. *P < 0.05. (F) Time on a rod rotating at 20 rpm. CP2-treated PS1 (orange, n = 5) and APP (dark blue, n = 5); untreated APP (light blue, n = 10), PS1 (gray, n = 10), and NTG mice (black, n = 10). Mice were 56 weeks old. *P < 0.05. (G, H) NOR test demonstrates that CP2-treated APP (G, light orange bars: training session; red bars: NOR, n = 5) and PS1 (H, light blue bars: training session; dark blue bars: NOR, n = 5) mice maintained the ability to recognize a familiar object similar to NTG animals (n = 10) while their untreated counterparts (n = 10 for APP and n = 10 for PS1) lost that ability with age. *P < 0.05. See also Figs. S1 and S2.
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f0005: Chronic CP2 treatment averts the development of behavior and memory phenotype in FAD mice.(A) CP2 structure. (B) P and F1 animals treated with 25 mg/kg/day CP2 produced F1 progeny that were treated with CP2 till 14 months of age. F2 pups were used for axonal trafficking experiments. (C, D) CP2-treated PS1 (C, light gray; n = 5) and APP (D, light gray, n = 5) mice maintained body weight similar to NTG untreated mice (black, n = 10), while untreated PS1 (C, dark gray, n = 10) and APP (D, dark gray, n = 10) mice accumulated weight with age. *P < 0.05. (E) CP2-treated APP mice (red, n = 5) did not display muscle weakness or altered prehensile reflex in hanging bar test compared to untreated APP animals (gray, n = 10). Black — untreated NTG, n = 10. *P < 0.05. (F) Time on a rod rotating at 20 rpm. CP2-treated PS1 (orange, n = 5) and APP (dark blue, n = 5); untreated APP (light blue, n = 10), PS1 (gray, n = 10), and NTG mice (black, n = 10). Mice were 56 weeks old. *P < 0.05. (G, H) NOR test demonstrates that CP2-treated APP (G, light orange bars: training session; red bars: NOR, n = 5) and PS1 (H, light blue bars: training session; dark blue bars: NOR, n = 5) mice maintained the ability to recognize a familiar object similar to NTG animals (n = 10) while their untreated counterparts (n = 10 for APP and n = 10 for PS1) lost that ability with age. *P < 0.05. See also Figs. S1 and S2.
Mentions: We have previously identified small molecule tricyclic pyrone CP2 (Fig. 1A) that protects cells against Aβ toxicity, and reduces brain Aβ in 5 × FAD mice (Hong et al., 2009; Maezawa et al., 2006). To examine the molecular mechanism, we first tested whether CP2 penetrates the blood–brain barrier (BBB). C14-Labeled CP2 was injected intraperitoneally to wild type (WT) mice, and levels were measured in the brain tissue 30 min post-injection (Fig. S1A, B). Results suggest that CP2 rapidly accumulates in the brain. Additional pharmacokinetics studies conducted in plasma of WT mice after intravenous or oral administration demonstrated that CP2 bioavailability is 43% (Fig. S1C, D).

Bottom Line: Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress.Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice.Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.

ABSTRACT

Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

No MeSH data available.


Related in: MedlinePlus