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

cris.virtual.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
cris.virtual.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
cris.virtual.author-orcid0000-0001-5845-4409
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cris.virtualsource.author-orcid#PLACEHOLDER_PARENT_METADATA_VALUE#
cris.virtualsource.author-orcid4dde7a12-8c22-4e89-9d57-7c74b050ccc5
dc.abstract.enBackground: 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
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Biotechnologii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.contributor.authorUtyro, Olga
dc.contributor.authorWłoczkowska-Łapińska, Olga
dc.contributor.authorJakubowski, Hieronim
dc.date.access2024-11-04
dc.date.accessioned2024-11-06T11:49:29Z
dc.date.available2024-11-06T11:49:29Z
dc.date.copyright2024-09-24
dc.date.issued2024
dc.description.abstract<jats:p>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-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–/–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 Aβ and worsened memory/sensorimotor performance in Blmh–/–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.</jats:p>
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0.00
dc.description.if3,4
dc.description.number3
dc.description.points100
dc.description.versionfinal_published
dc.description.volume101
dc.identifier.doi10.3233/JAD-240512
dc.identifier.eissn1875-8908
dc.identifier.issn1387-2877
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/1993
dc.identifier.weblinkhttps://content.iospress.com/articles/journal-of-alzheimers-disease/jad240512
dc.languageen
dc.relation.ispartofJournal of Alzheimer's Disease
dc.relation.pages823-834
dc.rightsCC-BY
dc.sciencecloudsend
dc.subject.enAlzheimer’s disease
dc.subject.enamyloid-beta
dc.subject.enamyloid-beta protein precursor
dc.subject.enautophagy
dc.subject.enbleomycin hydrolase
dc.subject.enBlmh–/–5xFAD mouse
dc.subject.enGLOD4
dc.subject.enN2a-APPswe mouse neuroblastoma cells
dc.titleAssociation of GLOD4 with Alzheimer’s Disease in Humans and Mice
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.issue3
oaire.citation.volume101