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Cited by 142Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer's disease

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Sangineto, Moris, Ciarnelli, Martina, Cassano, Tommaso, Radesco, Antonio, Moola, Archana, Bukke, Vidyasagar Naik, Romano, Antonino, Villani, Rosanna +5 more·2023·Redox Biology
DOI 10.1016/j.redox.2023.102846PMC PMC10457454
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Abstract

Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development.

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  • Therapeutic innovation in Alzheimer's disease is increasingly moving toward immune rebalancing and metabolic reprogramming.

    “Therapeutic innovation is increasingly moving toward immune rebalancing and metabolic reprogramming [179].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [179]

    The Discussion identifies microglial metabolic reprogramming as a promising way to control inflammation in early Alzheimer's disease, and the Results report a shift in inflammatory markers after metabolic intervention in mice. The paper does not establish that therapeutic innovation is increasingly moving in this direction across the field; it also finds this approach ineffective in advanced disease. Page numbers were not provided in our copy. (LLM, conf=0.86)

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Authors
Sangineto, M., Ciarnelli, M., Cassano, T., Radesco, A., Moola, A., Bukke, V. N., Romano, A., Villani, R., Kanwal, H., Capitanio, N., Duda, L., Avolio, C., & Serviddio, G.
Affiliations
  • University of Foggia (IT)
  • Istituto Tumori Bari (IT)
Corresponding author
Sangineto, Moris
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2023-10
Volume
66
Pages
102846
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2023.102846
PMC
PMC10457454
OpenAlex
W4385704195
Cited by
142
References
9
Citations by year
2026: 65 · 2025: 47 · 2024: 28 · 2023: 2
FWCI
14.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, microglia, metabolic reprogramming, succinate dehydrogenase, dimethyl malonate, LPS, mitochondrial dysfunction, glycolysis, electron transport chain, reactive oxygen species, HIF-1α, mitochondrial biogenesis, TLR4, neuroinflammation, 3xTg-AD mice, 5xFAD mice, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Inflammation, Lipopolysaccharides, Mice, Transgenic, Microglia, Toll-Like Receptor 4, Mice

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