1f23bfde32aa1f98aea4074fe0a8178d pmc_9103818.pdf db5b0ec0fa0bf1ec32660fb15007854f52199a85 pmc_9103818.pdf 299ce3bfc849c260acfb72fdc6fd2eda6a8a67c4e10da1cb3cb163f4b5b71a1c pmc_9103818.pdf Title: Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral -Amyloidosis: A Neuropathological Study Subject: The pathological accumulation of parenchymal and vascular amyloid-beta (A) are the main hallmarks of Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-A therapies in this field. Transgenic mice models of cerebral -amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular A deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of A-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible A presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal A deposition and to evaluate future disease-modifying therapy before its translation to the clinic. Keywords: APP23; 5xFAD; cerebral -amyloidosis; preclinical MRI; cerebral microbleeds Author: Paula Marazuela, Berta Paez-Montserrat, Anna Bonaterra-Pastra, Montse Solé and Mar Hernández-Guillamon Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri May 6 11:23:59 2022 CEST ModDate: Fri May 6 11:51:09 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2380909 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EQJVKE+EURB10 Type 1 Builtin yes yes no 10 0 GIFXFT+VnURWPalladioL-Bold Type 1 Custom yes yes no 14 0 UEHGBQ+VnURWPalladioL Type 1 Custom yes yes no 19 0 BBSDEQ+EURM10 Type 1 Builtin yes yes no 23 0 FGVVRD+URWPalladioL-Bold Type 1 Custom yes yes no 27 0 JYWXKW+URWPalladioL-Roma Type 1 Custom yes 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LUIHSM+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 249 0 FRDNMY+TimesNewRomanPSMT TrueType WinAnsi yes yes yes 253 0 HEGEOU+TimesNewRomanPS-BoldMT TrueType WinAnsi yes yes yes 257 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 267 0 TEDYAW+TimesNewRomanPSMT CID TrueType Identity-H yes yes yes 274 0 PIJFWE+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 282 0 SMYCMY+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 286 0 LUIHSM+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 290 0 CMVAWE+TimesNewRomanPS-ItalicMT TrueType WinAnsi yes yes yes 294 0 FRDNMY+TimesNewRomanPSMT TrueType WinAnsi yes yes yes 298 0 HEGEOU+TimesNewRomanPS-BoldMT TrueType WinAnsi yes yes yes 302 0 QMDDXF+CMSY10 Type 1 Builtin yes yes no 320 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-06-11 02:49:01 CEST RepresentationInformation: pmc_9103818.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-05-31 06:21:58 CEST Size: 2380909 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 606 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Levels of Parenchymal A Deposition Destination: subsection.2.1 Item: Title: Levels of Vascular A Deposition Destination: subsection.2.2 Item: Title: Analysis of A40 and A42 Deposition Destination: subsection.2.3 Item: Title: Determination of CAA-Related Cerebral Microbleeds Destination: subsection.2.4 Item: Title: Discussion Destination: section.3 Item: Title: Material and Methods Destination: section.4 Children: Item: Title: Transgenic Animals Destination: subsection.4.1 Item: Title: Tissue Processing for Histological Analysis Destination: subsection.4.2 Item: Title: Tissue Processing for Magnetic Resonance Imaging Destination: subsection.4.3 Item: Title: MRI Protocol and Analysis Destination: subsection.4.4 Item: Title: Thioflavin S Staining Destination: subsection.4.5 Item: Title: Resorufin Staining Destination: subsection.4.6 Item: Title: A Peptide Immunohistochemistry Destination: subsection.4.7 Item: Title: Prussian Blue Staining Destination: subsection.4.8 Item: Title: Statistical Analysis Destination: subsection.4.9 Item: Title: References Destination: subsection.4.9 Info: Title: Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral -Amyloidosis: A Neuropathological Study Author: Paula Marazuela, Berta Paez-Montserrat, Anna Bonaterra-Pastra, Montse Solé and Mar Hernández-Guillamon Subject: The pathological accumulation of parenchymal and vascular amyloid-beta (A) are the main hallmarks of Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-A therapies in this field. Transgenic mice models of cerebral -amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular A deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of A-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible A presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal A deposition and to evaluate future disease-modifying therapy before its translation to the clinic. 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