Metabolic Plasticity of Astrocytes and Aging of the Brain

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(4), P. 941 - 941

Published: Feb. 21, 2019

As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from systemic circulation. In addition, have a robust enzymatic capacity glycolysis, glycogenesis lipid metabolism, managing support in brain parenchyma for consumption. Here, we review plasticity astrocyte energy metabolism under physiologic pathologic conditions, highlighting age-dependent dysfunctions. astrocytes, glycolysis regulated by noradrenaline insulin, respectively, while mitochondrial ATP production fatty acid oxidation influenced thyroid hormone. These regulations essential maintaining normal activities, impairments these processes may lead neurodegeneration cognitive decline. Metabolic is also associated with (re)activation process events. It likely that recently described neurodegenerative neuroprotective subpopulations reactive metabolize distinct substrates, this preference supposed explain some their impacts on processes. Importantly, properties astrocytic metabolic bear translational potential defining new diagnostic biomarkers novel therapeutic targets mitigate age-related

Language: Английский

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A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents

Nature Protocols, Journal Year: 2020, Volume and Issue: 15(8), P. 2301 - 2320

Published: July 6, 2020

Language: Английский

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A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Brain, Journal Year: 2021, Volume and Issue: 145(6), P. 1924 - 1938

Published: Dec. 14, 2021

Abstract The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration dementia. Locus dysfunction contributes to pathobiology experimental models, which can be rescued increasing norepinephrine transmission. To test augmentation as a potential disease-modifying therapy, we performed biomarker-driven phase II trial atomoxetine, clinically-approved transporter inhibitor, subjects mild cognitive impairment due disease. design was single-centre, 12-month double-blind crossover trial. Thirty-nine participants and biomarker evidence were randomized atomoxetine or placebo treatment. Assessments collected at baseline, 6- (crossover) 12-months (completer). Target engagement assessed CSF plasma measures metabolites. Prespecified primary outcomes levels IL1α TECK. Secondary/exploratory included clinical measures, analyses amyloid-β42, Tau, pTau181, mass spectrometry proteomics immune-based targeted inflammation-related cytokines, well brain imaging MRI fluorodeoxyglucose-PET. Baseline demographic similar across arms. Dropout rates 5.1% for 2.7% placebo, no significant differences adverse events. Atomoxetine robustly increased levels. IL-1α TECK not measurable most samples. There treatment effects on cognition outcomes, expected given short duration. associated reduction pTau181 compared but change amyloid-β42. also significantly altered abundances protein panels linked pathophysiologies, including synaptic, metabolism glial immunity, CDCP1, CD244, TWEAK osteoprotegerin proteins. Treatment brain-derived neurotrophic factor reduced triglycerides plasma. Resting state functional showed inter-network connectivity between insula hippocampus. Fluorodeoxyglucose-PET atomoxetine-associated uptake hippocampus, parahippocampal gyrus, middle temporal pole, inferior gyrus fusiform carry-over 6 months after In summary, safe, tolerated achieved target prodromal pTau, normalized synaptic function, activity key lobe circuits. Further study warranted repurposing drug slow progression.

Language: Английский

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Sleep and circadian rhythms in Parkinson’s disease and preclinical models

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Jan. 9, 2022

The use of animals as models human physiology is, and has been for many years, an indispensable tool understanding the mechanisms disease. In Parkinson's disease, various mouse form cornerstone these investigations. Early were developed to reflect traditional histological features motor symptoms However, it is important that accurately encompass facets disease allow comprehensive mechanistic translational significance. Circadian rhythm sleep issues are tightly correlated often arise prior presentation typical deficits. It essential used understand dysfunctions in circadian rhythms sleep, both facilitate investigations into interplay between assist development rhythm-facing therapeutic treatments. This review describes extent which genetically- neurotoxically-induced murine abnormalities observed clinic.

Language: Английский

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Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 47(5), P. 1128 - 1136

Published: Feb. 17, 2022

Language: Английский

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