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Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.
- Source :
-
Cell reports [Cell Rep] 2024 Jul 23; Vol. 43 (7), pp. 114488. Date of Electronic Publication: 2024 Jul 13. - Publication Year :
- 2024
-
Abstract
- Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Humans
NF-kappa B metabolism
Mice, Transgenic
Signal Transduction
NF-KappaB Inhibitor alpha metabolism
Mitochondria metabolism
Mitochondria drug effects
Inflammation pathology
Inflammation metabolism
Brain pathology
Brain metabolism
Glycolysis drug effects
Gene Dosage
Hexokinase metabolism
Alzheimer Disease drug therapy
Alzheimer Disease pathology
Alzheimer Disease metabolism
Microglia metabolism
Microglia drug effects
Microglia pathology
Disease Progression
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 39002124
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114488