{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T22:38:21Z","timestamp":1780958301126,"version":"3.54.1"},"reference-count":56,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:p>Background: Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in Alzheimer\u2019s 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-\u03b2 (A\u03b2) 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 A\u03b2PP were quantified by western blotting and the corresponding mRNAs by RT-qPCR. A\u03b2 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 A\u03b2PP were upregulated while autophagy markers Becn1, Atg5, and Atg7 were downregulated in Blmh-\/- and Blmh-\/-5xFAD brains. A\u03b2 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 A\u03b2 without affecting A\u03b2PP. Conclusions: Our findings show that Blmh interacts with A\u03b2PP and the Phf8\/H4K20me1\/mTOR\/autophagy pathway, and that disruption of those interactions causes A\u03b2 accumulation and cognitive\/neuromotor deficits.<\/jats:p>","DOI":"10.3233\/jad-230578","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T13:43:19Z","timestamp":1694526199000},"page":"1735-1755","source":"Crossref","is-referenced-by-count":11,"title":["Deletion of the Homocysteine Thiolactone Detoxifying Enzyme Bleomycin Hydrolase, in Mice, Causes Memory and Neurological Deficits and Worsens Alzheimer\u2019s Disease-Related Behavioral and Biochemical Traits in the 5xFAD Model of Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"95","author":[{"given":"\u0141ukasz","family":"Witucki","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Pozna\u0144 University of Life Sciences, Pozna\u0144, Poland"},{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, International Center for Public Health, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Borowczyk","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, International Center for Public Health, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Suszy\u0144ska-Zajczyk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Pozna\u0144 University of Life Sciences, Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Warzych","sequence":"additional","affiliation":[{"name":"Department of Genetics and Animal Breeding, Pozna\u0144 University of Life Sciences, Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Genetics and Animal Breeding, Pozna\u0144 University of Life Sciences, Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieronim","family":"Jakubowski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Pozna\u0144 University of Life Sciences, Pozna\u0144, Poland"},{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, International Center for Public Health, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-230578_ref1","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.1021\/bi960092y","article-title":"Human bleomycin hydrolase: Molecular cloning, sequencing, functional expression, and enzymatic characterization","volume":"35","author":"Bromme","year":"1996","journal-title":"Biochemistry"},{"key":"10.3233\/JAD-230578_ref2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1093\/jb\/mvm005","article-title":"Quantification of neutral cysteine protease bleomycin hydrolase and its localization in rat tissues","volume":"141","author":"Kamata","year":"2007","journal-title":"J Biochem"},{"key":"10.3233\/JAD-230578_ref3","doi-asserted-by":"crossref","first-page":"22485","DOI":"10.1074\/jbc.M603656200","article-title":"Protective mechanisms against homocysteine toxicity: The role of bleomycin hydrolase","volume":"281","author":"Zimny","year":"2006","journal-title":"J Biol Chem"},{"key":"10.3233\/JAD-230578_ref4","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s00726-011-1207-5","article-title":"Metabolism and neurotoxicity of homocysteine thiolactone in mice: Protective role of bleomycin hydrolase","volume":"43","author":"Borowczyk","year":"2012","journal-title":"Amino Acids"},{"key":"10.3233\/JAD-230578_ref5","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/wrna.122","article-title":"Quality control in tRNA charging","volume":"3","author":"Jakubowski","year":"2012","journal-title":"Wiley Interdiscip Rev RNA"},{"key":"10.3233\/JAD-230578_ref6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1152\/physrev.00003.2018","article-title":"Homocysteine modification in protein structure\/function and human disease","volume":"99","author":"Jakubowski","year":"2019","journal-title":"Physiol Rev"},{"key":"10.3233\/JAD-230578_ref7","doi-asserted-by":"crossref","first-page":"149","DOI":"10.18388\/abp.2011_2259","article-title":"Quality control in tRNA charging \u2013editing of homocysteine","volume":"58","author":"Jakubowski","year":"2011","journal-title":"Acta Biochim Pol"},{"key":"10.3233\/JAD-230578_ref8","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/S0021-9258(19)67504-6","article-title":"Metabolism of homocysteine thiolactone in human cell cultures. 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