Association of GLOD4 with Alzheimer’s Disease in Humans and Mice

Abstract

AbstractBackgroundGlyoxalase 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.ObjectiveTo 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 ofBlmh−/−5xFAD mouse AD model of AD.MethodsGLOD4 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.Glod4gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4 protein/mRNA, Aβ precursor protein (Aβpp)/mRNA,Atg5,p62, andLc3mRNAs were quantified.ResultsGLOD4mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls.Glod4mRNA was downregulated in brains ofBlmh−/−5xFAD mice compared toBlmh+/+5xFAD sibling controls, but not inBlmh−/−mice without the 5xFAD transgene compared toBlmh+/+sibling controls. The 5xFAD transgene downregulated Glod4 mRNA inBlmh−/−mice of both sexes and inBlmh+/+males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance inBlmh−/−5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP and downregulated autophagy-relatedAtg5,p62, andLc3genes.ConclusionsThese 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.