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

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–/–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-(A) 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, A precursor protein (App), 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 nonAD 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 and worsened memory/sensorimotor performance in Blmh–/–5xFAD mice. Glod4 depletion in
N2a-APPswe cells upregulated APP, and downregulated autophagy-related Atg5, p62, and Lc3 genes.
Conclusions: These findings suggest that GLOD4 interacts with APP and the autophagy pathway, and that disruption of
these interactions leads to A accumulation and cognitive/neurosensory deficits