Neuron‐glia (mis)interactions in brain energy metabolism during aging

Mayorga-Weber, Gonzalo A.; Rivera, Francisco J.; Castro, Maite A.

doi:10.1002/jnr.25015

Cited by 14 publications

(11 citation statements)

References 266 publications

(239 reference statements)

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“…The elevated ATP concentration seen in these participants was hypothesized to result from astrocytic glycolysis in the setting of neuronal degeneration [39]. Astrocytes, serving as supportive cells, provide trophic metabolites and ATP to diseased neurons, and in response to exigent neuronal energetic needs, can transition to a glycolytic and oxidative energy-producing "overdrive" state to pump out excess ATP [40]. In this theory of attempted ATP compensation, the nding of high concentrations of ATP in a PD brain could point to neuronal crisis, rather than health [39].…”

Section: Discussionmentioning

confidence: 99%

Brain Target Engagement by CNM-Au8 in Parkinson’s Disease and Multiple Sclerosis: Integrated Imaging Results from the REPAIR-PD and REPAIR-MS Phase 2 Clinical Trials

Ren,

III,

Rynders

et al. 2023

Preprint

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Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson’s disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination in multiple, independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or PD, respectively. Brain metabolites were measured using 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14 for the PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including beta-ATP and phosphorylation potential across both cohorts. Results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.

show abstract

Section: Discussionmentioning

confidence: 99%

Brain Target Engagement by CNM-Au8 in Parkinson’s Disease and Multiple Sclerosis: Integrated Imaging Results from the REPAIR-PD and REPAIR-MS Phase 2 Clinical Trials

Ren,

III,

Rynders

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The elevated ATP concentration seen in these participants was hypothesized to result from astrocytic glycolysis in the setting of neuronal degeneration (40). Astrocytes, serving as supportive cells, provide trophic metabolites and ATP to diseased neurons, and in response to exigent neuronal energetic needs, can transition to a glycolytic and oxidative energy-producing "overdrive" state to pump out excess ATP (41). In this theory of attempted ATP compensation, the nding of high concentrations of ATP in a PD brain could point to neuronal crisis, rather than health (40).…”

Section: Discussionmentioning

confidence: 99%

Evidence of Brain Target Engagement in Parkinson’s Disease and Multiple Sclerosis by the Investigational Nanomedicine, CNM-Au8, in the REPAIR Phase 2 Clinical Trials

Ren,

Dewey,

Rynders

et al. 2023

Preprint

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Background Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson’s disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively. Results Brain metabolites were measured using 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including β-ATP and phosphorylation potential across both cohorts. Conclusions Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.

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“…Astrocytes are identified to account for about 5%-15% of the brain’s energy expenditure, while their energy consumption becomes higher in non-resting states [ 21 , 33 , 34 ]. Astrocytes absorb glucose mainly through GLUT1 and convert it into lactic acid which is oxidized in mitochondria [ 28 ], and this action is related with the phosphorylation of pyruvate dehydrogenase (PH.D.) and the activity of cytochrome oxidase in astrocytes [ 35 ].…”

Section: The Energy Dysmetabolism In Alzheimer’s Disease Brainmentioning

confidence: 99%

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer’s Disease: Current Evidence and Future Avenues

Fan

Wang

2023

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, and autophagy plays important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD, and discussed the interplays existing between energy crisis, autophagy and ferroptosis. In addition, we highlighted the potential network that autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new strategies for treating AD, meanwhile, the energy crisis in the progression of AD should gain more attention.

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Neuron‐glia (mis)interactions in brain energy metabolism during aging

Cited by 14 publications

References 266 publications

Brain Target Engagement by CNM-Au8 in Parkinson’s Disease and Multiple Sclerosis: Integrated Imaging Results from the REPAIR-PD and REPAIR-MS Phase 2 Clinical Trials

Brain Target Engagement by CNM-Au8 in Parkinson’s Disease and Multiple Sclerosis: Integrated Imaging Results from the REPAIR-PD and REPAIR-MS Phase 2 Clinical Trials

Evidence of Brain Target Engagement in Parkinson’s Disease and Multiple Sclerosis by the Investigational Nanomedicine, CNM-Au8, in the REPAIR Phase 2 Clinical Trials

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer’s Disease: Current Evidence and Future Avenues

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