Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease
Myeloperoxidase (MPO) is a key enzyme in inflammatory and degenerative processes, although conflicting reports have been presented concerning its expression in the brain. We studied the cellular localization of MPO and compared numbers of MPO cells in various brain regions between neurologically hea...
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Veröffentlicht in: | Cell and tissue research 2017-09, Vol.369 (3), p.445-454 |
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description | Myeloperoxidase (MPO) is a key enzyme in inflammatory and degenerative processes, although conflicting reports have been presented concerning its expression in the brain. We studied the cellular localization of MPO and compared numbers of MPO cells in various brain regions between neurologically healthy individuals and patients with Parkinson’s disease (PD) or Alzheimer’s disease (AD;
n
= 10–25). We also investigated two rodent PD models. MPO immunoreactivity (ir) was detected in monocytes, perivascular macrophages and amoeboid microglia in the human brain parenchyma, whereas no co-localization with glial fibrillary acidic protein (GFAP) ir was observed. In the midbrain, caudate and putamen, we found a significant increase of MPO-immunoreactive cells in PD compared with control brains, whereas in the cerebellum, no difference was apparent. MPO ir was detected neither in neurons nor in occasional small beta-amyloid-immunoreactive plaques in PD or control cases. In the frontal cortex of AD patients, we found significantly more MPO-immunoreactive cells compared with control cases, together with intense MPO ir in extracellular plaques. In the hippocampus of several AD cases, MPO-like ir was observed in some pyramidal neurons. Neither rapid dopamine depletion in the rat PD model, nor slow degeneration of dopamine neurons in MitoPark mice induced the expression of MPO ir in any brain region. MPO mRNA was not detectable with radioactive in situ hybridization in any human or rodent brain area, although myeloid cells from bone marrow displayed clear MPO signals. Our results indicate significant increases of MPO-immunoreactive cells in brain regions affected by neurodegeneration in PD and AD, supporting investigations of MPO inhibitors in novel treatment strategies. |
doi_str_mv | 10.1007/s00441-017-2626-8 |
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n
= 10–25). We also investigated two rodent PD models. MPO immunoreactivity (ir) was detected in monocytes, perivascular macrophages and amoeboid microglia in the human brain parenchyma, whereas no co-localization with glial fibrillary acidic protein (GFAP) ir was observed. In the midbrain, caudate and putamen, we found a significant increase of MPO-immunoreactive cells in PD compared with control brains, whereas in the cerebellum, no difference was apparent. MPO ir was detected neither in neurons nor in occasional small beta-amyloid-immunoreactive plaques in PD or control cases. In the frontal cortex of AD patients, we found significantly more MPO-immunoreactive cells compared with control cases, together with intense MPO ir in extracellular plaques. In the hippocampus of several AD cases, MPO-like ir was observed in some pyramidal neurons. Neither rapid dopamine depletion in the rat PD model, nor slow degeneration of dopamine neurons in MitoPark mice induced the expression of MPO ir in any brain region. MPO mRNA was not detectable with radioactive in situ hybridization in any human or rodent brain area, although myeloid cells from bone marrow displayed clear MPO signals. Our results indicate significant increases of MPO-immunoreactive cells in brain regions affected by neurodegeneration in PD and AD, supporting investigations of MPO inhibitors in novel treatment strategies.</description><identifier>ISSN: 0302-766X</identifier><identifier>EISSN: 1432-0878</identifier><identifier>DOI: 10.1007/s00441-017-2626-8</identifier><identifier>PMID: 28466093</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Advertising executives ; Aged ; Aged, 80 and over ; Alzheimer disease ; Alzheimer Disease - enzymology ; Alzheimer Disease - pathology ; Alzheimer's disease ; Analysis ; Animal models ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Bone marrow ; Brain ; Brain - enzymology ; Brain - pathology ; Cellular biology ; Cerebellum ; Cortex (frontal) ; Dopamine ; Enzymes ; Female ; frontal lobe ; Glial fibrillary acidic protein ; hippocampus ; Human Genetics ; Humans ; Immunoreactivity ; in situ hybridization ; Inflammation ; Localization ; Macrophages ; Male ; Mesencephalon ; messenger RNA ; mice ; Microglia ; Middle Aged ; Molecular Medicine ; Monocytes ; Movement disorders ; mRNA ; Myeloid cells ; myeloperoxidase ; Nerve Degeneration - enzymology ; Nerve Degeneration - pathology ; Neurodegeneration ; Neurodegenerative diseases ; neuroglia ; Neurons ; Parenchyma ; parenchyma (animal tissue) ; Parkinson disease ; Parkinson Disease - enzymology ; Parkinson Disease - pathology ; Parkinson's disease ; patients ; Peroxidase ; Peroxidase - metabolism ; Plaques ; Proteomics ; Putamen ; rats ; Rats, Sprague-Dawley ; Regular ; Regular Article ; β-Amyloid</subject><ispartof>Cell and tissue research, 2017-09, Vol.369 (3), p.445-454</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Springer</rights><rights>Cell and Tissue Research is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c705t-7d7b1aed51b3c44ee23a927e8144e7c735510a6f9abf83bcf59d856d8e5381573</citedby><cites>FETCH-LOGICAL-c705t-7d7b1aed51b3c44ee23a927e8144e7c735510a6f9abf83bcf59d856d8e5381573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00441-017-2626-8$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00441-017-2626-8$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28466093$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:136501529$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Gellhaar, Sandra</creatorcontrib><creatorcontrib>Sunnemark, Dan</creatorcontrib><creatorcontrib>Eriksson, Håkan</creatorcontrib><creatorcontrib>Olson, Lars</creatorcontrib><creatorcontrib>Galter, Dagmar</creatorcontrib><title>Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease</title><title>Cell and tissue research</title><addtitle>Cell Tissue Res</addtitle><addtitle>Cell Tissue Res</addtitle><description>Myeloperoxidase (MPO) is a key enzyme in inflammatory and degenerative processes, although conflicting reports have been presented concerning its expression in the brain. We studied the cellular localization of MPO and compared numbers of MPO cells in various brain regions between neurologically healthy individuals and patients with Parkinson’s disease (PD) or Alzheimer’s disease (AD;
n
= 10–25). We also investigated two rodent PD models. MPO immunoreactivity (ir) was detected in monocytes, perivascular macrophages and amoeboid microglia in the human brain parenchyma, whereas no co-localization with glial fibrillary acidic protein (GFAP) ir was observed. In the midbrain, caudate and putamen, we found a significant increase of MPO-immunoreactive cells in PD compared with control brains, whereas in the cerebellum, no difference was apparent. MPO ir was detected neither in neurons nor in occasional small beta-amyloid-immunoreactive plaques in PD or control cases. In the frontal cortex of AD patients, we found significantly more MPO-immunoreactive cells compared with control cases, together with intense MPO ir in extracellular plaques. In the hippocampus of several AD cases, MPO-like ir was observed in some pyramidal neurons. Neither rapid dopamine depletion in the rat PD model, nor slow degeneration of dopamine neurons in MitoPark mice induced the expression of MPO ir in any brain region. MPO mRNA was not detectable with radioactive in situ hybridization in any human or rodent brain area, although myeloid cells from bone marrow displayed clear MPO signals. Our results indicate significant increases of MPO-immunoreactive cells in brain regions affected by neurodegeneration in PD and AD, supporting investigations of MPO inhibitors in novel treatment strategies.</description><subject>Advertising executives</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alzheimer disease</subject><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bone marrow</subject><subject>Brain</subject><subject>Brain - enzymology</subject><subject>Brain - pathology</subject><subject>Cellular biology</subject><subject>Cerebellum</subject><subject>Cortex (frontal)</subject><subject>Dopamine</subject><subject>Enzymes</subject><subject>Female</subject><subject>frontal lobe</subject><subject>Glial fibrillary acidic protein</subject><subject>hippocampus</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoreactivity</subject><subject>in situ hybridization</subject><subject>Inflammation</subject><subject>Localization</subject><subject>Macrophages</subject><subject>Male</subject><subject>Mesencephalon</subject><subject>messenger RNA</subject><subject>mice</subject><subject>Microglia</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Monocytes</subject><subject>Movement disorders</subject><subject>mRNA</subject><subject>Myeloid cells</subject><subject>myeloperoxidase</subject><subject>Nerve Degeneration - enzymology</subject><subject>Nerve Degeneration - pathology</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>neuroglia</subject><subject>Neurons</subject><subject>Parenchyma</subject><subject>parenchyma (animal tissue)</subject><subject>Parkinson disease</subject><subject>Parkinson Disease - enzymology</subject><subject>Parkinson Disease - pathology</subject><subject>Parkinson's disease</subject><subject>patients</subject><subject>Peroxidase</subject><subject>Peroxidase - metabolism</subject><subject>Plaques</subject><subject>Proteomics</subject><subject>Putamen</subject><subject>rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Regular</subject><subject>Regular Article</subject><subject>β-Amyloid</subject><issn>0302-766X</issn><issn>1432-0878</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><recordid>eNqFkt-K1DAUxoso7rj6AN5IQVi86XrSNE1zIwyL_2BFLxS8C2l62slum4xJuzpe-Rj6ej6JqTOuM6JIoT39zu98nJycJLlP4JQA8McBoChIBoRneZmXWXUjWZCC5hlUvLqZLIBCnvGyfH-U3AnhAoAUZSluJ0d5FQMQdJF8fbXB3q3Ru0-mUQEzMwyTdR6VHs0Vphr7PqTKYxpMZ01rtLJjv0mN1ZEJ2MQorb2KbzULqWpb1GPU601qcfKuwQ4tejUaZ2f4jfKXxgZnv3_5FnHbpMv-8wrNgP6n0pgwG99NbrWqD3hv9z1O3j17-vbsRXb--vnLs-V5pjmwMeMNr4nChpGa6qJAzKkSOceKxB-uOWWMgCpboeq2orVumWgqVjYVMloRxulxkm19w0dcT7VcezMov5FOGbmTLmOEshAceBX5J1s-ZgZsNNrRq_6g7DBjzUp27koyxgXheTR4tDPw7sOEYZSDCfOYlUU3BZkDAGOClOy_KKlEEUEo57Ye_oFeuMnbODlJBC0IE_G8v6lO9SiNbV1sUc-mcskg51AQOnd4-hcqPg0ORjuLrYn6QcHJXsEKVT-uguun-crDIUi2oPYuBI_t9dwIyHml5XalZVxpOa-0nHt-sD_w64pfOxyBfHeDMWU79HtH_6frD3yFBYU</recordid><startdate>20170901</startdate><enddate>20170901</enddate><creator>Gellhaar, Sandra</creator><creator>Sunnemark, Dan</creator><creator>Eriksson, Håkan</creator><creator>Olson, Lars</creator><creator>Galter, Dagmar</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SS</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20170901</creationdate><title>Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease</title><author>Gellhaar, Sandra ; Sunnemark, Dan ; Eriksson, Håkan ; Olson, Lars ; Galter, Dagmar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c705t-7d7b1aed51b3c44ee23a927e8144e7c735510a6f9abf83bcf59d856d8e5381573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Advertising executives</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alzheimer disease</topic><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bone marrow</topic><topic>Brain</topic><topic>Brain - enzymology</topic><topic>Brain - pathology</topic><topic>Cellular biology</topic><topic>Cerebellum</topic><topic>Cortex (frontal)</topic><topic>Dopamine</topic><topic>Enzymes</topic><topic>Female</topic><topic>frontal lobe</topic><topic>Glial fibrillary acidic protein</topic><topic>hippocampus</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunoreactivity</topic><topic>in situ hybridization</topic><topic>Inflammation</topic><topic>Localization</topic><topic>Macrophages</topic><topic>Male</topic><topic>Mesencephalon</topic><topic>messenger RNA</topic><topic>mice</topic><topic>Microglia</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Monocytes</topic><topic>Movement disorders</topic><topic>mRNA</topic><topic>Myeloid cells</topic><topic>myeloperoxidase</topic><topic>Nerve Degeneration - enzymology</topic><topic>Nerve Degeneration - pathology</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>neuroglia</topic><topic>Neurons</topic><topic>Parenchyma</topic><topic>parenchyma (animal tissue)</topic><topic>Parkinson disease</topic><topic>Parkinson Disease - enzymology</topic><topic>Parkinson Disease - pathology</topic><topic>Parkinson's disease</topic><topic>patients</topic><topic>Peroxidase</topic><topic>Peroxidase - metabolism</topic><topic>Plaques</topic><topic>Proteomics</topic><topic>Putamen</topic><topic>rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Regular</topic><topic>Regular Article</topic><topic>β-Amyloid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gellhaar, Sandra</creatorcontrib><creatorcontrib>Sunnemark, Dan</creatorcontrib><creatorcontrib>Eriksson, Håkan</creatorcontrib><creatorcontrib>Olson, Lars</creatorcontrib><creatorcontrib>Galter, Dagmar</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Cell and tissue research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gellhaar, Sandra</au><au>Sunnemark, Dan</au><au>Eriksson, Håkan</au><au>Olson, Lars</au><au>Galter, Dagmar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease</atitle><jtitle>Cell and tissue research</jtitle><stitle>Cell Tissue Res</stitle><addtitle>Cell Tissue Res</addtitle><date>2017-09-01</date><risdate>2017</risdate><volume>369</volume><issue>3</issue><spage>445</spage><epage>454</epage><pages>445-454</pages><issn>0302-766X</issn><eissn>1432-0878</eissn><abstract>Myeloperoxidase (MPO) is a key enzyme in inflammatory and degenerative processes, although conflicting reports have been presented concerning its expression in the brain. We studied the cellular localization of MPO and compared numbers of MPO cells in various brain regions between neurologically healthy individuals and patients with Parkinson’s disease (PD) or Alzheimer’s disease (AD;
n
= 10–25). We also investigated two rodent PD models. MPO immunoreactivity (ir) was detected in monocytes, perivascular macrophages and amoeboid microglia in the human brain parenchyma, whereas no co-localization with glial fibrillary acidic protein (GFAP) ir was observed. In the midbrain, caudate and putamen, we found a significant increase of MPO-immunoreactive cells in PD compared with control brains, whereas in the cerebellum, no difference was apparent. MPO ir was detected neither in neurons nor in occasional small beta-amyloid-immunoreactive plaques in PD or control cases. In the frontal cortex of AD patients, we found significantly more MPO-immunoreactive cells compared with control cases, together with intense MPO ir in extracellular plaques. In the hippocampus of several AD cases, MPO-like ir was observed in some pyramidal neurons. Neither rapid dopamine depletion in the rat PD model, nor slow degeneration of dopamine neurons in MitoPark mice induced the expression of MPO ir in any brain region. MPO mRNA was not detectable with radioactive in situ hybridization in any human or rodent brain area, although myeloid cells from bone marrow displayed clear MPO signals. Our results indicate significant increases of MPO-immunoreactive cells in brain regions affected by neurodegeneration in PD and AD, supporting investigations of MPO inhibitors in novel treatment strategies.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>28466093</pmid><doi>10.1007/s00441-017-2626-8</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Advertising executives Aged Aged, 80 and over Alzheimer disease Alzheimer Disease - enzymology Alzheimer Disease - pathology Alzheimer's disease Analysis Animal models Animals Biomedical and Life Sciences Biomedicine Bone marrow Brain Brain - enzymology Brain - pathology Cellular biology Cerebellum Cortex (frontal) Dopamine Enzymes Female frontal lobe Glial fibrillary acidic protein hippocampus Human Genetics Humans Immunoreactivity in situ hybridization Inflammation Localization Macrophages Male Mesencephalon messenger RNA mice Microglia Middle Aged Molecular Medicine Monocytes Movement disorders mRNA Myeloid cells myeloperoxidase Nerve Degeneration - enzymology Nerve Degeneration - pathology Neurodegeneration Neurodegenerative diseases neuroglia Neurons Parenchyma parenchyma (animal tissue) Parkinson disease Parkinson Disease - enzymology Parkinson Disease - pathology Parkinson's disease patients Peroxidase Peroxidase - metabolism Plaques Proteomics Putamen rats Rats, Sprague-Dawley Regular Regular Article β-Amyloid |
title | Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease |
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