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Association of GLOD4 with Alzheimer's Disease in Humans and Mice.
- Source :
- Journal of Alzheimer's Disease; 2024, Vol. 101 Issue 3, p823-834, 12p
- Publication Year :
- 2024
-
Abstract
- Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer's disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4's association with AD was unknown. Objective: To assess GLOD4's role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh<superscript>–/–</superscript>5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4, Aβ precursor protein (Aβpp), Atg5, p62, and Lc3 proteins and mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh<superscript>–/–</superscript>5xFAD mice compared to Blmh<superscript>+/+</superscript>5xFAD sibling controls, but not in Blmh<superscript>–/–</superscript> mice without the 5xFAD transgene compared to Blmh<superscript>+/+</superscript> sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh<superscript>–/–</superscript> mice of both sexes and in Blmh<superscript>+/+</superscript> males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh<superscript>–/–</superscript>5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5, p62, and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 13872877
- Volume :
- 101
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Journal of Alzheimer's Disease
- Publication Type :
- Academic Journal
- Accession number :
- 180007759
- Full Text :
- https://doi.org/10.3233/JAD-240512