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Deletion of the Homocysteine Thiolactone Detoxifying Enzyme Bleomycin Hydrolase, in Mice, Causes Memory and Neurological Deficits and Worsens Alzheimer’s Disease-Related Behavioral and Biochemical Traits in the 5xFAD Model of Alzheimer’s Disease

cris.lastimport.scopus2025-10-23T06:56:17Z
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cris.virtual.author-orcid0000-0001-6384-791X
cris.virtual.author-orcid0000-0003-3489-1684
cris.virtual.author-orcid0000-0001-5845-4409
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cris.virtualsource.author-orcid02a0d8c3-755b-4ed1-a428-3e47baa39519
cris.virtualsource.author-orcid4ed4e453-28dc-48e8-864d-49bd28fdc14e
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dc.abstract.enBackground: Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in Alzheimer’s disease (AD) brains. Blmh loss causes astrogliosis in mice while the loss of histone demethylase Phf8, which controls mTOR signaling, causes neuropathy in mice and humans. Objective: To examine how Blmh gene deletion affects the Phf8/H4K20me1/mTOR/autophagy pathway, amyloid-β (Aβ) accumulation, and cognitive/neuromotor performance in mice. Methods: We generated a new mouse model of AD, the Blmh-/-5xFAD mouse. Behavioral assessments were conducted by cognitive/neuromotor testing. Blmh and Phf8 genes were silenced in mouse neuroblastoma N2a-APPswe cells by RNA interference. mTOR- and autophagy-related proteins, and AβPP were quantified by western blotting and the corresponding mRNAs by RT-qPCR. Aβ was quantified by western blotting (brains) and by confocal microscopy (cells). Results: Behavioral testing showed cognitive/neuromotor deficits in Blmh-/- and Blmh-/-5xFAD mice. Phf8 was transcriptionally downregulated in Blmh-/- and Blmh-/-5xFAD brains. H4K20me1, mTOR, phospho-mTOR, and AβPP were upregulated while autophagy markers Becn1, Atg5, and Atg7 were downregulated in Blmh-/- and Blmh-/-5xFAD brains. Aβ was elevated in Blmh-/-5xFAD brains. These biochemical changes were recapitulated in Blmh-silenced N2a-APPswe cells, which also showed increased H4K20me1-mTOR promoter binding and impaired autophagy flux (Lc3-I, Lc3-II, p62). Phf8-silencing or treatments with Hcy-thiolactone or N-Hcy-protein, metabolites elevated in Blmh-/- mice, induced biochemical changes in N2a-APPswe cells like those induced by the Blmh-silencing. However, Phf8-silencing elevated Aβ without affecting AβPP.
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Bioinżynierii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.affiliation.instituteKatedra Genetyki i Podstaw Hodowli Zwierząt​​
dc.contributor.authorWitucki, Łukasz
dc.contributor.authorBorowczyk, Kamila
dc.contributor.authorSuszyńska-Zajczyk, Joanna
dc.contributor.authorWarzych-Plejer, Ewelina
dc.contributor.authorPawlak, Piotr
dc.contributor.authorJakubowski, Hieronim
dc.date.access2025-08-26
dc.date.accessioned2025-08-26T11:25:42Z
dc.date.available2025-08-26T11:25:42Z
dc.date.copyright2023-09-12
dc.date.issued2023
dc.description.abstract<jats:p>Background: Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in Alzheimer’s disease (AD) brains. Blmh loss causes astrogliosis in mice while the loss of histone demethylase Phf8, which controls mTOR signaling, causes neuropathy in mice and humans. Objective: To examine how Blmh gene deletion affects the Phf8/H4K20me1/mTOR/autophagy pathway, amyloid-β (Aβ) accumulation, and cognitive/neuromotor performance in mice. Methods: We generated a new mouse model of AD, the Blmh-/-5xFAD mouse. Behavioral assessments were conducted by cognitive/neuromotor testing. Blmh and Phf8 genes were silenced in mouse neuroblastoma N2a-APPswe cells by RNA interference. mTOR- and autophagy-related proteins, and AβPP were quantified by western blotting and the corresponding mRNAs by RT-qPCR. Aβ was quantified by western blotting (brains) and by confocal microscopy (cells). Results: Behavioral testing showed cognitive/neuromotor deficits in Blmh-/- and Blmh-/-5xFAD mice. Phf8 was transcriptionally downregulated in Blmh-/- and Blmh-/-5xFAD brains. H4K20me1, mTOR, phospho-mTOR, and AβPP were upregulated while autophagy markers Becn1, Atg5, and Atg7 were downregulated in Blmh-/- and Blmh-/-5xFAD brains. Aβ was elevated in Blmh-/-5xFAD brains. These biochemical changes were recapitulated in Blmh-silenced N2a-APPswe cells, which also showed increased H4K20me1-mTOR promoter binding and impaired autophagy flux (Lc3-I, Lc3-II, p62). Phf8-silencing or treatments with Hcy-thiolactone or N-Hcy-protein, metabolites elevated in Blmh-/- mice, induced biochemical changes in N2a-APPswe cells like those induced by the Blmh-silencing. However, Phf8-silencing elevated Aβ without affecting AβPP. Conclusions: Our findings show that Blmh interacts with AβPP and the Phf8/H4K20me1/mTOR/autophagy pathway, and that disruption of those interactions causes Aβ accumulation and cognitive/neuromotor deficits.</jats:p>
dc.description.accesstimeat_publication
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0,00
dc.description.if3,4
dc.description.number4
dc.description.points100
dc.description.versionfinal_published
dc.description.volume95
dc.identifier.doi10.3233/JAD-230578
dc.identifier.eissn1875-8908
dc.identifier.issn1387-2877
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/4382
dc.identifier.weblinkhttps://journals.sagepub.com/doi/10.3233/JAD-230578
dc.languageen
dc.relation.ispartofJournal of Alzheimer's Disease
dc.relation.pages1735-1755
dc.rightsCC-BY
dc.sciencecloudsend
dc.share.typeOTHER
dc.subject.enAlzheimers diseas
dc.subject.enamyloid-β protein precursor
dc.subject.enautophagy
dc.subject.enbleomycin hydrolase
dc.subject.enBlmh-/-5xFAD mouse
dc.subject.enH4K20me1
dc.subject.enhomocysteine thiolactone
dc.subject.enmTOR
dc.subject.enN2a-APPswe mouse neuroblastoma cells
dc.subject.enPhf8
dc.titleDeletion of the Homocysteine Thiolactone Detoxifying Enzyme Bleomycin Hydrolase, in Mice, Causes Memory and Neurological Deficits and Worsens Alzheimer’s Disease-Related Behavioral and Biochemical Traits in the 5xFAD Model of Alzheimer’s Disease
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.issue4
oaire.citation.volume95