Abstract:Biochemical alterations underlying the symptoms and pathomechanisms of Alzheimer's disease (AD) are not fully understood. However, alterations of glucose metabolism and mitochondrial dysfunction certainly play an important role. (1)H- and (13)C-NMR spectroscopy exhibits promising results in providing information about those alterations in vivo in patients and animals, especially regarding the mitochondrial tricarboxylic acid (TCA) cycle. Accordingly, transgenic mice expressing mutant human amyloid precursor pr… Show more
“…1 H-[ 13 C]-NMR spectroscopy analyses of the APP swe -PS1dE9 mouse model of AD showed a decrease in glutamate, GABA, and glutamine, which suggested an impaired glutamatergic and GABAergic glucose oxidation and neurotransmitter cycle in these mouse brains [78]. 1 H- 13 C spectroscopy analyses of Thy-1-APPSL model, expressing mutant human APP, suggested that mitochondrial dysfunction may contributed to the glutamine synthetase impairment and increased metabolism of glutamate via the GABA shunt [79]. Glucose metabolism was clearly reduced by ~50% in a 3xTG-AD model as exhibited by the decreased levels of metabolites derived from the TCA cycle (glutamate, glutamine, GABA, and NAA) [80].…”
Section: Energy Metabolism In Brain Aging and Alzheimer’s Diseasementioning
The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies.
“…1 H-[ 13 C]-NMR spectroscopy analyses of the APP swe -PS1dE9 mouse model of AD showed a decrease in glutamate, GABA, and glutamine, which suggested an impaired glutamatergic and GABAergic glucose oxidation and neurotransmitter cycle in these mouse brains [78]. 1 H- 13 C spectroscopy analyses of Thy-1-APPSL model, expressing mutant human APP, suggested that mitochondrial dysfunction may contributed to the glutamine synthetase impairment and increased metabolism of glutamate via the GABA shunt [79]. Glucose metabolism was clearly reduced by ~50% in a 3xTG-AD model as exhibited by the decreased levels of metabolites derived from the TCA cycle (glutamate, glutamine, GABA, and NAA) [80].…”
Section: Energy Metabolism In Brain Aging and Alzheimer’s Diseasementioning
The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies.
“…We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD [ 36 ]. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPP SL mice which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD [ 37 , 38 ]. Fig.…”
BackgroundCurrent approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.MethodsThree-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.ResultsMH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.ConclusionsMH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0342-6) contains supplementary material, which is available to authorized users.
“…This led to a decrease in the flux of glucose being converted into TCA cycle metabolites, a process critical to generating neurotransmitters and maintaining synaptic plasticity. In fact, metabolic alterations in these mitochondrial TCA cycle metabolites have been demonstrated in different rodent models of Alzheimer's disease (Dedeoglu et al 2004;Marjanska et al 2005;Salek et al 2010;Esteras et al 2012;Tiwari & Patel, 2012;Haris et al 2013;Nilsen et al 2013;van Duijn et al 2013;Doert et al 2015) and clinical cases (Lin et al 2003). These studies suggest that both lowered brain glucose uptake and alternations in mitochondrial TCA cycle function contribute to the hypometabolic state observed in ageing and Alzheimer's disease.…”
Mitochondrial dysfunction entailing decreased energy-transducing capacity and perturbed redox homeostasis is an early and sometimes initiating event in ageing and age-related disorders involving tissues with high metabolic rate such as brain, liver and heart. In the central nervous system (CNS), recent findings from our and other groups suggest that the mitochondrion-centred hypometabolism is a key feature of ageing brains and Alzheimer's disease. This hypometabolic state is manifested by lowered neuronal glucose uptake, metabolic shift in the astrocytes, and alternations in mitochondrial tricarboxylic acid cycle function. Similarly, in liver and adipose tissue, mitochondrial capacity around glucose and fatty acid metabolism and thermogenesis is found to decline with age and is implicated in age-related metabolic disorders such as obesity and type 2 diabetes mellitus. These mitochondrion-related disorders in peripheral tissues can impact on brain functions through metabolic, hormonal and inflammatory signals. At the cellular level, studies in CNS and non-CNS tissues support the notion that instead of being viewed as autonomous organelles, mitochondria are part of a dynamic network with close interactions with other cellular components through energy-or redox-sensitive cytosolic kinase signalling and transcriptional pathways. Hence, it would be critical to further understand the molecular mechanisms involved in the communication between mitochondria and the rest of the cell. Therapeutic strategies that effectively preserves or improve mitochondrial function by targeting key component of these signalling cascades could represent a novel direction for numerous mitochondrion-implicated, age-related disorders.
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