Tau immunotherapy is associated with glial responses in FTLD-tau
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized...
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| Veröffentlicht in: | Acta neuropathologica 2021-08, Vol.142 (2), p.243-257 |
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| creator | Kim, Boram Mikytuck, Bailey Suh, Eunran Gibbons, Garrett S. Van Deerlin, Vivianna M. Vaishnavi, Sanjeev N. Spindler, Meredith A. Massimo, Lauren Grossman, Murray Trojanowski, John Q. Irwin, David J. Lee, Edward B. |
| description | Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes. |
| doi_str_mv | 10.1007/s00401-021-02318-y |
| format | Article |
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Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.</description><identifier>ISSN: 0001-6322</identifier><identifier>EISSN: 1432-0533</identifier><identifier>DOI: 10.1007/s00401-021-02318-y</identifier><identifier>PMID: 33950293</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Aged ; Aged, 80 and over ; Aging ; Animal models ; Astrocytes ; Astrocytes - immunology ; Astrocytes - metabolism ; Astrocytes - pathology ; Brain ; Brain - immunology ; Brain - pathology ; Cerebrospinal fluid ; Clinical trials ; Complications ; Frontotemporal dementia ; Frontotemporal Lobar Degeneration - drug therapy ; Frontotemporal Lobar Degeneration - metabolism ; Genetic engineering ; Gliosis ; Humans ; Immunohistochemistry ; Immunotherapy ; Lysosomes ; Lysosomes - metabolism ; Male ; Medicine ; Medicine & Public Health ; Microglia ; Middle Aged ; Monoclonal antibodies ; Neurodegeneration ; Neurodegenerative diseases ; Neuroglia - immunology ; Neuroglia - metabolism ; Neuroglia - pathology ; Neuronal-glial interactions ; Neurons - pathology ; Neuropathology ; Neurosciences ; Original Paper ; Paralysis ; Pathology ; Plaques ; Progressive supranuclear palsy ; Rodents ; Tau protein ; tau Proteins - immunology ; tau Proteins - metabolism ; Tauopathies - drug therapy ; Tauopathies - immunology ; Tauopathies - pathology ; Transgenic mice</subject><ispartof>Acta neuropathologica, 2021-08, Vol.142 (2), p.243-257</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>COPYRIGHT 2021 Springer</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-303049c6bb34cd478e05523d3aafa30ad85188d6a62a8faa3fd7368604c35d3f3</citedby><cites>FETCH-LOGICAL-c541t-303049c6bb34cd478e05523d3aafa30ad85188d6a62a8faa3fd7368604c35d3f3</cites><orcidid>0000-0002-4589-1180</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00401-021-02318-y$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00401-021-02318-y$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33950293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Boram</creatorcontrib><creatorcontrib>Mikytuck, Bailey</creatorcontrib><creatorcontrib>Suh, Eunran</creatorcontrib><creatorcontrib>Gibbons, Garrett S.</creatorcontrib><creatorcontrib>Van Deerlin, Vivianna M.</creatorcontrib><creatorcontrib>Vaishnavi, Sanjeev N.</creatorcontrib><creatorcontrib>Spindler, Meredith A.</creatorcontrib><creatorcontrib>Massimo, Lauren</creatorcontrib><creatorcontrib>Grossman, Murray</creatorcontrib><creatorcontrib>Trojanowski, John Q.</creatorcontrib><creatorcontrib>Irwin, David J.</creatorcontrib><creatorcontrib>Lee, Edward B.</creatorcontrib><title>Tau immunotherapy is associated with glial responses in FTLD-tau</title><title>Acta neuropathologica</title><addtitle>Acta Neuropathol</addtitle><addtitle>Acta Neuropathol</addtitle><description>Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging</subject><subject>Animal models</subject><subject>Astrocytes</subject><subject>Astrocytes - immunology</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - pathology</subject><subject>Brain</subject><subject>Brain - immunology</subject><subject>Brain - pathology</subject><subject>Cerebrospinal fluid</subject><subject>Clinical trials</subject><subject>Complications</subject><subject>Frontotemporal dementia</subject><subject>Frontotemporal Lobar Degeneration - drug therapy</subject><subject>Frontotemporal Lobar Degeneration - metabolism</subject><subject>Genetic engineering</subject><subject>Gliosis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunotherapy</subject><subject>Lysosomes</subject><subject>Lysosomes - 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pathology</topic><topic>Neuropathology</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Paralysis</topic><topic>Pathology</topic><topic>Plaques</topic><topic>Progressive supranuclear palsy</topic><topic>Rodents</topic><topic>Tau protein</topic><topic>tau Proteins - immunology</topic><topic>tau Proteins - metabolism</topic><topic>Tauopathies - drug therapy</topic><topic>Tauopathies - immunology</topic><topic>Tauopathies - pathology</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Boram</creatorcontrib><creatorcontrib>Mikytuck, Bailey</creatorcontrib><creatorcontrib>Suh, Eunran</creatorcontrib><creatorcontrib>Gibbons, Garrett S.</creatorcontrib><creatorcontrib>Van Deerlin, Vivianna M.</creatorcontrib><creatorcontrib>Vaishnavi, Sanjeev N.</creatorcontrib><creatorcontrib>Spindler, Meredith A.</creatorcontrib><creatorcontrib>Massimo, Lauren</creatorcontrib><creatorcontrib>Grossman, Murray</creatorcontrib><creatorcontrib>Trojanowski, John Q.</creatorcontrib><creatorcontrib>Irwin, David J.</creatorcontrib><creatorcontrib>Lee, Edward B.</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>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma 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>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Psychology Database</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>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta neuropathologica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Boram</au><au>Mikytuck, Bailey</au><au>Suh, Eunran</au><au>Gibbons, Garrett S.</au><au>Van Deerlin, Vivianna M.</au><au>Vaishnavi, Sanjeev N.</au><au>Spindler, Meredith A.</au><au>Massimo, Lauren</au><au>Grossman, Murray</au><au>Trojanowski, John Q.</au><au>Irwin, David J.</au><au>Lee, Edward B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tau immunotherapy is associated with glial responses in FTLD-tau</atitle><jtitle>Acta neuropathologica</jtitle><stitle>Acta Neuropathol</stitle><addtitle>Acta Neuropathol</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>142</volume><issue>2</issue><spage>243</spage><epage>257</epage><pages>243-257</pages><issn>0001-6322</issn><eissn>1432-0533</eissn><abstract>Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>33950293</pmid><doi>10.1007/s00401-021-02318-y</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4589-1180</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta neuropathologica, 2021-08, Vol.142 (2), p.243-257 |
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| subjects | Aged Aged, 80 and over Aging Animal models Astrocytes Astrocytes - immunology Astrocytes - metabolism Astrocytes - pathology Brain Brain - immunology Brain - pathology Cerebrospinal fluid Clinical trials Complications Frontotemporal dementia Frontotemporal Lobar Degeneration - drug therapy Frontotemporal Lobar Degeneration - metabolism Genetic engineering Gliosis Humans Immunohistochemistry Immunotherapy Lysosomes Lysosomes - metabolism Male Medicine Medicine & Public Health Microglia Middle Aged Monoclonal antibodies Neurodegeneration Neurodegenerative diseases Neuroglia - immunology Neuroglia - metabolism Neuroglia - pathology Neuronal-glial interactions Neurons - pathology Neuropathology Neurosciences Original Paper Paralysis Pathology Plaques Progressive supranuclear palsy Rodents Tau protein tau Proteins - immunology tau Proteins - metabolism Tauopathies - drug therapy Tauopathies - immunology Tauopathies - pathology Transgenic mice |
| title | Tau immunotherapy is associated with glial responses in FTLD-tau |
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