Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes
Abstract Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for the...
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| Language: | English |
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BMC
2025-08-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02085-x |
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| author | Keiji Kawatani Tomonori Aikawa Zeynab Tabrizi Yining Pan Yingxue Ren Ni Wang Aishe Kurti Toshihiko Nambara Clark C. Ikezu Francis Shue Michael Bamkole Yasuteru Inoue Tammee M. Parsons Guojun Bu Qianqian Song Oliver Bracko Takahisa Kanekiyo |
| author_facet | Keiji Kawatani Tomonori Aikawa Zeynab Tabrizi Yining Pan Yingxue Ren Ni Wang Aishe Kurti Toshihiko Nambara Clark C. Ikezu Francis Shue Michael Bamkole Yasuteru Inoue Tammee M. Parsons Guojun Bu Qianqian Song Oliver Bracko Takahisa Kanekiyo |
| author_sort | Keiji Kawatani |
| collection | DOAJ |
| description | Abstract Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16 INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16 INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model. |
| format | Article |
| id | doaj-art-6e1e43c62b80456da1cf0b6991f1fb9e |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-6e1e43c62b80456da1cf0b6991f1fb9e2025-08-20T04:02:49ZengBMCActa Neuropathologica Communications2051-59602025-08-0113111910.1186/s40478-025-02085-xCerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypesKeiji Kawatani0Tomonori Aikawa1Zeynab Tabrizi2Yining Pan3Yingxue Ren4Ni Wang5Aishe Kurti6Toshihiko Nambara7Clark C. Ikezu8Francis Shue9Michael Bamkole10Yasuteru Inoue11Tammee M. Parsons12Guojun Bu13Qianqian Song14Oliver Bracko15Takahisa Kanekiyo16Department of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Biology, The University of MiamiDepartment of Health Outcomes & Biomedical Informatics, University of Florida College of MedicineDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Health Outcomes & Biomedical Informatics, University of Florida College of MedicineDepartment of Biology, The University of MiamiDepartment of Neuroscience, Mayo ClinicAbstract Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16 INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16 INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.https://doi.org/10.1186/s40478-025-02085-xAAVCerebral small vessel diseaseMousep16INK4ASenescenceVCID |
| spellingShingle | Keiji Kawatani Tomonori Aikawa Zeynab Tabrizi Yining Pan Yingxue Ren Ni Wang Aishe Kurti Toshihiko Nambara Clark C. Ikezu Francis Shue Michael Bamkole Yasuteru Inoue Tammee M. Parsons Guojun Bu Qianqian Song Oliver Bracko Takahisa Kanekiyo Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes Acta Neuropathologica Communications AAV Cerebral small vessel disease Mouse p16INK4A Senescence VCID |
| title | Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes |
| title_full | Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes |
| title_fullStr | Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes |
| title_full_unstemmed | Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes |
| title_short | Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes |
| title_sort | cerebrovascular p16ink4a expression induces cerebral small vessel disease related phenotypes |
| topic | AAV Cerebral small vessel disease Mouse p16INK4A Senescence VCID |
| url | https://doi.org/10.1186/s40478-025-02085-x |
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