Department of Neural Sciences, Alzheimer's Center at Temple, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
Aging Cell. 2024 May;23(5):e14106. doi: 10.1111/acel.14106. Epub 2024 Feb 15.
Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40-E22Q (AβQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)-mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ-induced cEC DR4/5-mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22-mediated activation of the DR4/5-mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome-c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, impairing VEGF-A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ-induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.
脑血管功能障碍被认为是阿尔茨海默病（AD）病理学的主要原因，大脑内皮细胞（cEC）应激会促进缺血、脑血流损伤和血脑屏障（BBB）通透性。最近的证据表明，心血管（CV）/脑血管危险因素，包括高同型半胱氨酸血症（Hhcy），会加重 AD 病理学和风险。然而，这种相互作用的潜在分子机制尚不清楚。我们的实验室已经证明，淀粉样蛋白β 40（Aβ40）物种，特别是 Aβ40-E22Q（AβQ22；血管病变荷兰突变体），促进人 cEC 中死亡受体 4 和 5（DR4/DR5）介导的细胞凋亡、屏障通透性和血管生成损伤。先前的研究表明，Hhcy 也会诱导内皮细胞功能障碍，但尚不清楚 Aβ 和同型半胱氨酸是否通过共同的分子机制发挥作用。我们检验了以下假设：Hhcy 加剧了 Aβ 诱导的 cEC DR4/5 介导的细胞凋亡、屏障功能障碍和血管生成缺陷。这项研究首次表明，Hhcy 特异性增强了 AβQ22 介导的 cEC 中 DR4/5 介导的外在细胞凋亡途径的激活，包括 DR4/5 表达、半胱天冬酶 8/9/3 激活、细胞色素 c 释放和 DNA 片段化。此外，我们揭示了 Hhcy 加剧了 Aβ 介导的同一 cEC 连接蛋白的失调，导致 BBB 通透性增加。此外，Hhcy 和 AβQ22 削弱了 VEGF-A/VEGFR2 信号转导和 VEGFR2 内体运输，从而降低了 cEC 的血管生成能力。总的来说，这些结果表明，CV 危险因素 Hhcy 的存在加剧了 Aβ 诱导的 cEC 细胞凋亡、屏障功能障碍和血管生成损伤。这项研究揭示了淀粉样蛋白和 Hhcy 共同作用产生脑内皮细胞功能障碍和死亡的具体机制，强调了针对 AD/CAA 和 Hhcy 合并症中血管病理学的新的潜在分子靶点。
