A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity

Knobloch, Marlen; Pilz, Gregor-Alexander; Ghesquière, Bart; Kovacs, Werner J.; Wegleiter, Thomas; Moore, Darcie L.; Hruzova, Martina; Zamboni, Nicola; Carmeliet, Peter; Jessberger, Sebastian

doi:10.1016/j.celrep.2017.08.029

Cited by 262 publications

(285 citation statements)

References 65 publications

(98 reference statements)

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“…As a proof of this notion, perturbation of mitochondrial function in quiescent radial glia‐like neural stem cells due to depletion of mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis . In addition, other evidences elucidated the metabolic changes between quiescent and proliferative NSCs , or in the transition from NSCs to NPCs . To date only few reports have addressed the role of mitochondria during the maturation process from neuroblasts to neurons , thus a detailed metabolic characterization of this transition is still incomplete.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

et al. 2019

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The metabolic transition from anaerobic glycolysis and fatty acid β‐oxidation to glycolysis coupled to oxidative phosphorylation is a key process for the transition of quiescent neural stem cells to proliferative neural progenitor cells. However, a full characterization of the metabolic shift and the involvement of mitochondria during the last step of neurogenesis, from neuroblasts to neuron maturation, is still elusive. Here, we describe a model of neuroblasts, Neuro2a cells, with impaired differentiation capacity due to mitochondrial dysfunction. Using a detailed biochemical characterization consisting of steady‐state metabolomics and metabolic flux analysis, we find increased fatty acid β‐oxidation as a peculiar feature of neuroblasts with altered mitochondria. The consequent metabolic switch favors neuroblast proliferation at the expense of neuron maturation.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

et al. 2019

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“…Astrocytes and NPCs are the main cell types in the brain that utilize FAO for their energy expenditure (Edmond, Robbins, Bergstrom, Cole, & de Vellis, 1987;Knobloch et al, 2017) and FAs have been shown to be produced endogenously in neuronal stem cells (Knobloch et al, 2013). This prompted us to focus this study on astrocytes and NPCs.…”

Section: Discussionmentioning

confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate‐limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1‐mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742‐treated mice did not show altered astrocytic glial fibrillary acidic protein‐immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ‐induced impairment of long‐term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ‐agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

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“…It is widely supposed that brain did not use fatty acids as energy substrates (Panov et al, 2014;Schönfeld and Reiser, 2013). However, although this is true for neurons, the carnitine palmitoyl transferase (CPT) system, which allows the entry of long-chain fatty acids into the mitochondria for ß-oxidation, is functional in astrocytes (Jernberg et al, 2017;Panov et al, 2014) and in embryonic (Xie et al, 2016) and adult (Knobloch et al, 2017) neural stem cells. The role of carnitine in its anti-inflammatory or energetic functions remains to be elucidated in this model and may constitute for the future a starting point for the development of innovative therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

Vetel

Sérrière

Vercouillie

et al. 2018

Synapse

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Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6‐hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH‐positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.

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A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity

Cited by 262 publications

References 65 publications

Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

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