Kawatani Keiji, Aikawa Tomonori, Tabrizi Zeynab, Pan Yining, Ren Yingxue, Wang Ni, Kurti Aishe, Nambara Toshihiko, Ikezu Clark C, Shue Francis, Bamkole Michael, Inoue Yasuteru, Parsons Tammee M, Bu Guojun, Song Qianqian, Bracko Oliver, Kanekiyo Takahisa
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Department of Biology, The University of Miami, Coral Gables, FL, 33146, USA.
Acta Neuropathol Commun. 2025 Aug 12;13(1):171. doi: 10.1186/s40478-025-02085-x.
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 in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16 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 p16 in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.
脑小血管病（cSVD）是血管性认知障碍和痴呆（VCID）最常见的病因，且与阿尔茨海默病的发病机制高度相关。迫切需要建立cSVD的相关动物模型。由于衰老为这些疾病最强的风险因素，脑血管衰老与cSVD的发病机制有关。我们研究了基于腺相关病毒（AAV）在脑血管内皮细胞中表达衰老标志物CDKN2A/p16如何影响成年野生型小鼠的cSVD表型。单次腹腔注射携带CDKN2A/p16的AAV会导致血脑屏障受损、神经血管解偶联和脑血流量减少，并伴有小鼠行为改变。单细胞RNA测序和免疫染色显示脑血管内皮细胞中血管细胞黏附分子1（VCAM1）上调，而体内双光子激发显微镜检测到白细胞与毛细血管的黏附加剧。我们的研究结果通过新的小鼠模型证明了脑血管内皮细胞中的p16对cSVD和VCID发病机制的作用。
