Association of GLOD4 with Alzheimers Disease in Humans and Mice

BackgroundGlyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimers disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4s association with AD was unknown. ObjectiveTo assess GLOD4s 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-/-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 {beta} (A{beta}) 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 protein/mRNA, A{beta} precursor protein (A{beta}pp)/mRNA, Atg5, p62, and Lc3 mRNAs were quantified. ResultsGLOD4 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-/-5xFAD mice compared to Blmh+/+5xFAD sibling controls, but not in Blmh-/- mice without the 5xFAD transgene compared to Blmh+/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh-/- mice of both sexes and in Blmh+/+ males but not females. Attenuated Glod4 was associated with elevated A{beta} and worsened memory/sensorimotor performance in Blmh-/-5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated A{beta}PP and downregulated autophagy-related Atg5, p62, and Lc3 genes. ConclusionsThese findings suggest that GLOD4 interacts with A{beta}PP and the autophagy pathway, and that disruption of these interactions leads to A{beta} accumulation and cognitive/neurosensory deficits.