a053d93c58db38fba4ae09a60e0cabf0 pmc_34356892.pdf 0b8a42ecbf4a42b81c23b18bad63dc4e0c9db65a pmc_34356892.pdf d5072d955571568480bf937719fd93f57cf68a7b0c5c9bc0fade5ea35492a977 pmc_34356892.pdf Title: Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia Subject: Monomeric C-reactive protein (mCRP), the activated isoform of CRP, induces tissue damage in a range of inflammatory pathologies. Its detection in infarcted human brain tissue and its experimentally proven ability to promote dementia with Alzheimer’s disease (AD) traits at 4 weeks after intrahippocampal injection in mice have suggested that it may contribute to the development of AD after cerebrovascular injury. Here, we showed that a single hippocampal administration of mCRP in mice induced memory loss, lasting at least 6 months, along with neurodegenerative changes detected by increased levels of hyperphosphorylated tau protein and a decrease of the neuroplasticity marker Egr1. Furthermore, co-treatment with the monoclonal antibody 8C10 specific for mCRP showed that long-term memory loss and tau pathology were entirely avoided by early blockade of mCRP. Notably, 8C10 mitigated Egr1 decrease in the mouse hippocampus. 8C10 also protected against mCRP-induced inflammatory pathways in a microglial cell line, as shown by the prevention of increased generation of nitric oxide. Additional in vivo and in vitro neuroprotective testing with the anti-inflammatory agent TPPU, an inhibitor of the soluble epoxide hydrolase enzyme, confirmed the predominant involvement of neuroinflammatory processes in the dementia induced by mCRP. Therefore, locally deposited mCRP in the infarcted brain may be a novel biomarker for AD prognosis, and its antibody blockade opens up therapeutic opportunities for reducing post-stroke AD risk. Keywords: monomeric C-reactive protein (mCRP); biomarker; Alzheimer’s disease; mouse model of mCRP dementia Author: Elisa García-Lara, Samuel Aguirre, Núria Clotet, Xenia Sawkulycz, Clara Bartra, Lidia Almenara-Fuentes, Cristina Suñol, Rubén Corpas, Peter Olah, Florin Tripon, Andrei Crauciuc, Mark Slevin and Coral Sanfeliu Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jul 19 04:04:52 2021 CEST ModDate: Mon Jul 19 04:11:02 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 23 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3288703 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- RMJXAG+VnURWPalladioL Type 1 Custom yes yes no 10 0 JCFYKI+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 GBYXWS+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 BWSAWI+URWPalladioL-Roma Type 1 Custom yes 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yes yes yes 330 0 CLPANC+TimesNewRoman,Italic TrueType WinAnsi yes yes no 336 0 CLPBHA+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 339 0 CLPBIC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 342 0 CLPALP+TimesNewRoman,Bold CID TrueType Identity-H yes yes yes 350 0 CLPBIE+PalatinoLinotype TrueType WinAnsi yes yes no 356 0 CLPANA+TimesNewRoman CID TrueType Identity-H yes yes yes 359 0 CLPANC+TimesNewRoman,Italic TrueType WinAnsi yes yes no 365 0 CLPBHA+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 368 0 CLPBIC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 371 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2021-09-11 02:57:18 CEST RepresentationInformation: pmc_34356892.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-08-09 03:33:57 CEST Size: 3288703 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 661 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Material and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Experimental Agents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Animals and Experimental Design Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Hippocampal Surgery and Treatment Administration Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Behavioral Testing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Western Blot Analysis of Hippocampus Tissue Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Quantitative PCR Analysis of Hippocampus Tissue Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Assays in the Microglial BV2 Cell Line Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: General Indicators of Body Health Were Not Modified by mCRP Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Anti-mCRP Antibody 8C10 Protected Against Anxiety Induced by mCRP at 6 Months of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Anti-mCRP Antibody 8C10 Protected against Loss of Recognition Memory Induced by mCRP at 1, 3 and 6 Months of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: TPPU Protected Against Loss of Recognition Memory Induced by mCRP at 1 Month of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Anti-mCRP Antibody 8C10 Protected Against Loss of Spatial Memory Induced by mCRP at 1, 3 and 6 Months of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: TPPU Protected against Loss of Spatial Memory Induced by mCRP at 1 Month of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Anti-mCRP Antibody 8C10 Inhibited Tau Hyperphosphorylation Induced by mCRP at 6 Months of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Anti-mCRP Antibody 8C10 Palliated the Decrease of a Neural Plasticity Marker by mCRP at 6 Months of Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Anti-mCRP Antibody 8C10 and TPPU Reduced Inflammatory Activation of BV2 Cells by mCRP Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Conclusions and Future Directions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Limitations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Info: Title: Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia Author: Elisa García-Lara, Samuel Aguirre, Núria Clotet, Xenia Sawkulycz, Clara Bartra, Lidia Almenara-Fuentes, Cristina Suñol, Rubén Corpas, Peter Olah, Florin Tripon, Andrei Crauciuc, Mark Slevin and Coral Sanfeliu Subject: Monomeric C-reactive protein (mCRP), the activated isoform of CRP, induces tissue damage in a range of inflammatory pathologies. Its detection in infarcted human brain tissue and its experimentally proven ability to promote dementia with Alzheimer’s disease (AD) traits at 4 weeks after intrahippocampal injection in mice have suggested that it may contribute to the development of AD after cerebrovascular injury. Here, we showed that a single hippocampal administration of mCRP in mice induced memory loss, lasting at least 6 months, along with neurodegenerative changes detected by increased levels of hyperphosphorylated tau protein and a decrease of the neuroplasticity marker Egr1. Furthermore, co-treatment with the monoclonal antibody 8C10 specific for mCRP showed that long-term memory loss and tau pathology were entirely avoided by early blockade of mCRP. Notably, 8C10 mitigated Egr1 decrease in the mouse hippocampus. 8C10 also protected against mCRP-induced inflammatory pathways in a microglial cell line, as shown by the prevention of increased generation of nitric oxide. Additional in vivo and in vitro neuroprotective testing with the anti-inflammatory agent TPPU, an inhibitor of the soluble epoxide hydrolase enzyme, confirmed the predominant involvement of neuroinflammatory processes in the dementia induced by mCRP. Therefore, locally deposited mCRP in the infarcted brain may be a novel biomarker for AD prognosis, and its antibody blockade opens up therapeutic opportunities for reducing post-stroke AD risk. 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