Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA, 90048, USA.
Department of Biomedical Sciences and Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Acta Neuropathol. 2020 May;139(5):813-836. doi: 10.1007/s00401-020-02134-w. Epub 2020 Feb 10.
Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aβ deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRβ in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ and Aβ burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.
周细胞缺失和血管血小板衍生生长因子受体-β（PDGFRβ）信号转导受损是阿尔茨海默病（AD）中血脑屏障破坏的显著特征，可预测认知能力下降，但从未在视网膜中进行过研究。最近的报告使用非侵入性视网膜淀粉样蛋白成像、光相干断层扫描血管造影和组织学检查支持 AD 患者视网膜存在血管结构异常和血管淀粉样β蛋白（Aβ）沉积。然而，这种视网膜血管病理学的细胞和分子机制以前并未被探索过。在这里，通过修改一种酶消化非血管视网膜组织和分离的血管网络荧光免疫标记的方法，我们发现 AD 患者的视网膜微血管和周细胞中存在大量周细胞缺失和明显的 Aβ沉积。对来自 56 名人类供体的死后视网膜的评估显示，与认知正常对照组相比，轻度认知障碍（MCI）和 AD 患者的血管 PDGFRβ 早期且逐渐减少。视网膜 PDGFRβ 丢失与视网膜血管 Aβ 和 Aβ 负担增加显著相关。还检测到 AD 视网膜中血管 LRP-1 减少和周细胞早期凋亡。在预先定义的视网膜亚区中对 PDGFRβ 和 Aβ 水平进行映射表明，某些几何和细胞层更容易受到 AD 病理学的影响。此外，还确定了视网膜血管异常与大脑 Aβ 负荷、脑淀粉样血管病（CAA）和临床状况之间的相关性。总之，AD 视网膜中周细胞和 PDGFRβ 缺失伴随血管淀粉样变性的发现表明血视网膜屏障完整性受损，并为 AD 的诊断和治疗提供了新的靶点。
