Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation
Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (...
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| Veröffentlicht in: | Theranostics 2021-01, Vol.11 (18), p.8964-8976 |
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| creator | Biechele, Gloria Blume, Tanja Deussing, Maximilian Zott, Benedikt Shi, Yuan Xiang, Xianyuan Franzmeier, Nicolai Kleinberger, Gernot Peters, Finn Ochs, Katharina Focke, Carola Sacher, Christian Wind, Karin Schmidt, Claudio Lindner, Simon Gildehaus, Franz-Josef Eckenweber, Florian Beyer, Leonie von Ungern-Sternberg, Barbara Bartenstein, Peter Baumann, Karlheinz Dorostkar, Mario M Rominger, Axel Cumming, Paul Willem, Michael Adelsberger, Helmuth Herms, Jochen Brendel, Matthias |
| description | Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation.
Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP,
). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal.
Pioglitazone-treated female PS2APP and
mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male
mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001).
TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification. |
| doi_str_mv | 10.7150/thno.64022 |
| format | Article |
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Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP,
). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal.
Pioglitazone-treated female PS2APP and
mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male
mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001).
TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.</description><identifier>ISSN: 1838-7640</identifier><identifier>EISSN: 1838-7640</identifier><identifier>DOI: 10.7150/thno.64022</identifier><identifier>PMID: 34522221</identifier><language>eng</language><publisher>Australia: Ivyspring International Publisher Pty Ltd</publisher><subject>Age ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Amyloidosis ; Animal memory ; Animals ; Brain ; Brain - diagnostic imaging ; Brain - metabolism ; Disease Models, Animal ; Experiments ; Female ; Hypotheses ; Immunity, Innate - immunology ; Immunomodulation - immunology ; Immunomodulation - physiology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia - metabolism ; Mutation ; Pioglitazone - pharmacology ; Positron-Emission Tomography - methods ; PPAR gamma - drug effects ; PPAR gamma - metabolism ; Receptors, GABA - metabolism ; Receptors, GABA - physiology ; Research Paper ; Rodents ; Sex Factors</subject><ispartof>Theranostics, 2021-01, Vol.11 (18), p.8964-8976</ispartof><rights>The author(s).</rights><rights>2021. This work is published under https://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><rights>The author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-265590d6bb714477b006c4aff03eb84bf78277114d6e90e342f5e3a3e27eed793</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419052/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419052/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34522221$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Biechele, Gloria</creatorcontrib><creatorcontrib>Blume, Tanja</creatorcontrib><creatorcontrib>Deussing, Maximilian</creatorcontrib><creatorcontrib>Zott, Benedikt</creatorcontrib><creatorcontrib>Shi, Yuan</creatorcontrib><creatorcontrib>Xiang, Xianyuan</creatorcontrib><creatorcontrib>Franzmeier, Nicolai</creatorcontrib><creatorcontrib>Kleinberger, Gernot</creatorcontrib><creatorcontrib>Peters, Finn</creatorcontrib><creatorcontrib>Ochs, Katharina</creatorcontrib><creatorcontrib>Focke, Carola</creatorcontrib><creatorcontrib>Sacher, Christian</creatorcontrib><creatorcontrib>Wind, Karin</creatorcontrib><creatorcontrib>Schmidt, Claudio</creatorcontrib><creatorcontrib>Lindner, Simon</creatorcontrib><creatorcontrib>Gildehaus, Franz-Josef</creatorcontrib><creatorcontrib>Eckenweber, Florian</creatorcontrib><creatorcontrib>Beyer, Leonie</creatorcontrib><creatorcontrib>von Ungern-Sternberg, Barbara</creatorcontrib><creatorcontrib>Bartenstein, Peter</creatorcontrib><creatorcontrib>Baumann, Karlheinz</creatorcontrib><creatorcontrib>Dorostkar, Mario M</creatorcontrib><creatorcontrib>Rominger, Axel</creatorcontrib><creatorcontrib>Cumming, Paul</creatorcontrib><creatorcontrib>Willem, Michael</creatorcontrib><creatorcontrib>Adelsberger, Helmuth</creatorcontrib><creatorcontrib>Herms, Jochen</creatorcontrib><creatorcontrib>Brendel, Matthias</creatorcontrib><title>Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation</title><title>Theranostics</title><addtitle>Theranostics</addtitle><description>Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation.
Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP,
). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal.
Pioglitazone-treated female PS2APP and
mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male
mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001).
TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.</description><subject>Age</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloidosis</subject><subject>Animal memory</subject><subject>Animals</subject><subject>Brain</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>Disease Models, Animal</subject><subject>Experiments</subject><subject>Female</subject><subject>Hypotheses</subject><subject>Immunity, Innate - immunology</subject><subject>Immunomodulation - immunology</subject><subject>Immunomodulation - physiology</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Microglia - metabolism</subject><subject>Mutation</subject><subject>Pioglitazone - pharmacology</subject><subject>Positron-Emission Tomography - methods</subject><subject>PPAR gamma - drug effects</subject><subject>PPAR gamma - metabolism</subject><subject>Receptors, GABA - metabolism</subject><subject>Receptors, GABA - physiology</subject><subject>Research Paper</subject><subject>Rodents</subject><subject>Sex Factors</subject><issn>1838-7640</issn><issn>1838-7640</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkU1LHTEUhkNp8Yp14w-QQDdFGJvPycymUKR-gNAudB0ymRNvLjPJNclI_fdGrxXbs0kOec7Le_IidETJqaKSfCvrEE9bQRj7gPZpx7tG1e7ju_sKHea8IbUq1dN-D624kKwW3UfD7wRNWUMyW1iKt3j2NsW7yRtsbPEPpvgYsAkjzvAHj1AgzT4A3o08YnAObMk4OmzXKYaq4Od5CXGO4zK9TH9Gn5yZMhy-ngfo9vznzdllc_3r4ursx3VjBWlLw1opezK2w6CoEEoNhLRWGOcIh6ETg1MdU4pSMbbQE-CCOQnccGAKYFQ9P0Dfd7rbZZhhtBBKMpPeJj-b9Kij8frfl-DX-i4-6E7QnkhWBb6-CqR4v0AuevbZwjSZAHHJmknFek67Tlb0y3_oJi4p1PUq1XeMUMlVpU52VP3SnBO4NzOU6Of09HN6-iW9Ch-_t_-G_s2KPwH20pd8</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Biechele, Gloria</creator><creator>Blume, Tanja</creator><creator>Deussing, Maximilian</creator><creator>Zott, Benedikt</creator><creator>Shi, Yuan</creator><creator>Xiang, Xianyuan</creator><creator>Franzmeier, Nicolai</creator><creator>Kleinberger, Gernot</creator><creator>Peters, Finn</creator><creator>Ochs, Katharina</creator><creator>Focke, Carola</creator><creator>Sacher, Christian</creator><creator>Wind, Karin</creator><creator>Schmidt, Claudio</creator><creator>Lindner, Simon</creator><creator>Gildehaus, Franz-Josef</creator><creator>Eckenweber, Florian</creator><creator>Beyer, Leonie</creator><creator>von Ungern-Sternberg, Barbara</creator><creator>Bartenstein, Peter</creator><creator>Baumann, Karlheinz</creator><creator>Dorostkar, Mario M</creator><creator>Rominger, Axel</creator><creator>Cumming, Paul</creator><creator>Willem, Michael</creator><creator>Adelsberger, Helmuth</creator><creator>Herms, Jochen</creator><creator>Brendel, Matthias</creator><general>Ivyspring International Publisher Pty Ltd</general><general>Ivyspring International Publisher</general><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>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210101</creationdate><title>Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation</title><author>Biechele, Gloria ; Blume, Tanja ; Deussing, Maximilian ; Zott, Benedikt ; Shi, Yuan ; Xiang, Xianyuan ; Franzmeier, Nicolai ; Kleinberger, Gernot ; Peters, Finn ; Ochs, Katharina ; Focke, Carola ; Sacher, Christian ; Wind, Karin ; Schmidt, Claudio ; Lindner, Simon ; Gildehaus, Franz-Josef ; Eckenweber, Florian ; Beyer, Leonie ; von Ungern-Sternberg, Barbara ; Bartenstein, Peter ; Baumann, Karlheinz ; Dorostkar, Mario M ; Rominger, Axel ; Cumming, Paul ; Willem, Michael ; Adelsberger, Helmuth ; Herms, Jochen ; Brendel, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-265590d6bb714477b006c4aff03eb84bf78277114d6e90e342f5e3a3e27eed793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Age</topic><topic>Alzheimer Disease - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Theranostics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Biechele, Gloria</au><au>Blume, Tanja</au><au>Deussing, Maximilian</au><au>Zott, Benedikt</au><au>Shi, Yuan</au><au>Xiang, Xianyuan</au><au>Franzmeier, Nicolai</au><au>Kleinberger, Gernot</au><au>Peters, Finn</au><au>Ochs, Katharina</au><au>Focke, Carola</au><au>Sacher, Christian</au><au>Wind, Karin</au><au>Schmidt, Claudio</au><au>Lindner, Simon</au><au>Gildehaus, Franz-Josef</au><au>Eckenweber, Florian</au><au>Beyer, Leonie</au><au>von Ungern-Sternberg, Barbara</au><au>Bartenstein, Peter</au><au>Baumann, Karlheinz</au><au>Dorostkar, Mario M</au><au>Rominger, Axel</au><au>Cumming, Paul</au><au>Willem, Michael</au><au>Adelsberger, Helmuth</au><au>Herms, Jochen</au><au>Brendel, Matthias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation</atitle><jtitle>Theranostics</jtitle><addtitle>Theranostics</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>11</volume><issue>18</issue><spage>8964</spage><epage>8976</epage><pages>8964-8976</pages><issn>1838-7640</issn><eissn>1838-7640</eissn><abstract>Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation.
Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP,
). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal.
Pioglitazone-treated female PS2APP and
mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male
mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001).
TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.</abstract><cop>Australia</cop><pub>Ivyspring International Publisher Pty Ltd</pub><pmid>34522221</pmid><doi>10.7150/thno.64022</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1838-7640 |
| ispartof | Theranostics, 2021-01, Vol.11 (18), p.8964-8976 |
| issn | 1838-7640 1838-7640 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8419052 |
| source | MEDLINE; PubMed Central Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Age Alzheimer Disease - metabolism Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloidosis Animal memory Animals Brain Brain - diagnostic imaging Brain - metabolism Disease Models, Animal Experiments Female Hypotheses Immunity, Innate - immunology Immunomodulation - immunology Immunomodulation - physiology Ligands Male Mice Mice, Inbred C57BL Mice, Transgenic Microglia - metabolism Mutation Pioglitazone - pharmacology Positron-Emission Tomography - methods PPAR gamma - drug effects PPAR gamma - metabolism Receptors, GABA - metabolism Receptors, GABA - physiology Research Paper Rodents Sex Factors |
| title | Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T21%3A31%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pre-therapeutic%20microglia%20activation%20and%20sex%20determine%20therapy%20effects%20of%20chronic%20immunomodulation&rft.jtitle=Theranostics&rft.au=Biechele,%20Gloria&rft.date=2021-01-01&rft.volume=11&rft.issue=18&rft.spage=8964&rft.epage=8976&rft.pages=8964-8976&rft.issn=1838-7640&rft.eissn=1838-7640&rft_id=info:doi/10.7150/thno.64022&rft_dat=%3Cproquest_pubme%3E2598201537%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2598201537&rft_id=info:pmid/34522221&rfr_iscdi=true |