DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease
Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clea...
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| Veröffentlicht in: | The Journal of pathology 2021-11, Vol.255 (3), p.296-310 |
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| creator | Choi, Chiyeol Park, Jiwon Kim, Hyerin Chang, Karen T Park, Jiyoung Min, Kyung‐Tai |
| description | Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1‐DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re‐establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| doi_str_mv | 10.1002/path.5767 |
| format | Article |
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Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1‐DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re‐establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.5767</identifier><identifier>PMID: 34312845</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid ; amyloid pathology ; Animals ; Calcineurin ; Calcium-Binding Proteins - metabolism ; Cognitive ability ; Down's syndrome ; DSCR1 ; Dura Mater - metabolism ; dural meningeal lymphatics ; Glymphatic System - metabolism ; Lymphatic drainage ; Lymphatic system ; Lymphatic Vessels ; Memory ; Meninges ; Mice ; Mice, Transgenic ; Muscle Proteins - metabolism ; Neurodegenerative diseases ; Pathology ; Plaque, Amyloid - pathology ; Senile plaques ; Sensory neurons ; Surgical drains ; Up-Regulation</subject><ispartof>The Journal of pathology, 2021-11, Vol.255 (3), p.296-310</ispartof><rights>2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</rights><rights>Copyright © 2021 Pathological Society of Great Britain and Ireland</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-3705-4769 ; 0000-0003-0983-4258</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpath.5767$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpath.5767$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34312845$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choi, Chiyeol</creatorcontrib><creatorcontrib>Park, Jiwon</creatorcontrib><creatorcontrib>Kim, Hyerin</creatorcontrib><creatorcontrib>Chang, Karen T</creatorcontrib><creatorcontrib>Park, Jiyoung</creatorcontrib><creatorcontrib>Min, Kyung‐Tai</creatorcontrib><title>DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease</title><title>The Journal of pathology</title><addtitle>J Pathol</addtitle><description>Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1‐DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re‐establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>amyloid pathology</subject><subject>Animals</subject><subject>Calcineurin</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cognitive ability</subject><subject>Down's syndrome</subject><subject>DSCR1</subject><subject>Dura Mater - metabolism</subject><subject>dural meningeal lymphatics</subject><subject>Glymphatic System - metabolism</subject><subject>Lymphatic drainage</subject><subject>Lymphatic system</subject><subject>Lymphatic Vessels</subject><subject>Memory</subject><subject>Meninges</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Muscle Proteins - metabolism</subject><subject>Neurodegenerative diseases</subject><subject>Pathology</subject><subject>Plaque, Amyloid - pathology</subject><subject>Senile plaques</subject><subject>Sensory neurons</subject><subject>Surgical drains</subject><subject>Up-Regulation</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kFtLw0AQhRdRbK0--AdkwQef0u4lm80-lnqpUFC0PodJMrmU3Ew2SPz1JlR9mgPn48zMIeSasyVnTKwasNlSaU-fkDlnxnOMb7xTMh894UiX6xm56LoDY8wYpc7JTLqSC99Vc2Lv3zdvnPZNi2lfgM3rimKVQRVhR-O-hYKWWOVViqMqhrLJRiaicQt5BSlSW1OwFqseLFIoh6LOYzrdUxd1OtA6oeviO8O8xPZuDMw7hA4vyVkCRYdXv3NBPh4f9puts3t5et6sd04jtNGOMsBDroV0UejIc9FVQjERg05ikCxMPK3dhBk_CjnzQAvNhRKJZrEnwDeJXJDbY27T1p89djY41H1bjSsDoXzGpJKuGKmbX6oPS4yDps1LaIfgr6QRWB2Br7zA4d_nLJjaD6Zvg6n94HW9305C_gAb5nfX</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Choi, Chiyeol</creator><creator>Park, Jiwon</creator><creator>Kim, Hyerin</creator><creator>Chang, Karen T</creator><creator>Park, Jiyoung</creator><creator>Min, Kyung‐Tai</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0003-3705-4769</orcidid><orcidid>https://orcid.org/0000-0003-0983-4258</orcidid></search><sort><creationdate>202111</creationdate><title>DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease</title><author>Choi, Chiyeol ; Park, Jiwon ; Kim, Hyerin ; Chang, Karen T ; Park, Jiyoung ; Min, Kyung‐Tai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2797-59a1b17234e27c64e452502da7fda30bf6774f098cb106a7271252f70d62a89f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid</topic><topic>amyloid pathology</topic><topic>Animals</topic><topic>Calcineurin</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cognitive ability</topic><topic>Down's syndrome</topic><topic>DSCR1</topic><topic>Dura Mater - metabolism</topic><topic>dural meningeal lymphatics</topic><topic>Glymphatic System - metabolism</topic><topic>Lymphatic drainage</topic><topic>Lymphatic system</topic><topic>Lymphatic Vessels</topic><topic>Memory</topic><topic>Meninges</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Muscle Proteins - metabolism</topic><topic>Neurodegenerative diseases</topic><topic>Pathology</topic><topic>Plaque, Amyloid - pathology</topic><topic>Senile plaques</topic><topic>Sensory neurons</topic><topic>Surgical drains</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choi, Chiyeol</creatorcontrib><creatorcontrib>Park, Jiwon</creatorcontrib><creatorcontrib>Kim, Hyerin</creatorcontrib><creatorcontrib>Chang, Karen T</creatorcontrib><creatorcontrib>Park, Jiyoung</creatorcontrib><creatorcontrib>Min, Kyung‐Tai</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choi, Chiyeol</au><au>Park, Jiwon</au><au>Kim, Hyerin</au><au>Chang, Karen T</au><au>Park, Jiyoung</au><au>Min, Kyung‐Tai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J Pathol</addtitle><date>2021-11</date><risdate>2021</risdate><volume>255</volume><issue>3</issue><spage>296</spage><epage>310</epage><pages>296-310</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><abstract>Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1‐DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re‐establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>34312845</pmid><doi>10.1002/path.5767</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-3705-4769</orcidid><orcidid>https://orcid.org/0000-0003-0983-4258</orcidid></addata></record> |
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| subjects | Alzheimer Disease - pathology Alzheimer's disease Amyloid amyloid pathology Animals Calcineurin Calcium-Binding Proteins - metabolism Cognitive ability Down's syndrome DSCR1 Dura Mater - metabolism dural meningeal lymphatics Glymphatic System - metabolism Lymphatic drainage Lymphatic system Lymphatic Vessels Memory Meninges Mice Mice, Transgenic Muscle Proteins - metabolism Neurodegenerative diseases Pathology Plaque, Amyloid - pathology Senile plaques Sensory neurons Surgical drains Up-Regulation |
| title | DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease |
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