Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; GnomeDX, Powell, OH, USA.
Rutgers University Hospital Department of Pathology, Newark, NY, USA.
Ann Diagn Pathol. 2022 Dec;61:152057. doi: 10.1016/j.anndiagpath.2022.152057. Epub 2022 Oct 28.
Pre-existing Alzheimer's disease is a risk factor for severe/fatal COVID-19 and infection by SARS-CoV2 virus has been associated with an increased incidence of un-masked Alzheimer's disease. The molecular basis whereby SARS-CoV2 may amplify Alzheimer's disease is not well understood. This study analyzed the molecular changes in autopsy brain tissues from people with pre-existing dementia who died of COVID-19 (n = 5) which was compared to equivalent tissues of people who died of COVID-19 with no history of dementia (n = 8), Alzheimer's disease pre-COVID-19 (n = 10) and aged matched controls (n = 10) in a blinded fashion. Immunohistochemistry analyses for hyperphosphorylated tau protein, α-synuclein, and β-amyloid-42 confirmed the diagnoses of Alzheimer's disease (n = 4), and Lewy body dementia (n = 1) in the COVID-19 group. The brain tissues from patients who died of COVID-19 with no history of dementia showed a diffuse microangiopathy marked by endocytosis of spike subunit S1 and S2 in primarily CD31+ endothelia with strong co-localization with ACE2, Caspase-3, IL6, TNFα, and Complement component 6 that was not associated with SARS-CoV2 RNA. Microglial activation marked by increased TMEM119 and MCP1 protein expression closely paralleled the endocytosed spike protein. The COVID-19 tissues from people with no pre-existing dementia showed, compared to controls, 5-10× fold increases in expression of neuronal NOS and NMDAR2 as well as a marked decrease in the expression of proteins whose loss is associated with worsening Alzheimer's disease: MFSD2a, SHIP1, BCL6, BCL10, and BACH1. In COVID-19 tissues from people with dementia the widespread spike-induced microencephalitis with the concomitant microglial activation co-existed in the same areas where neurons had hyperphosphorylated tau protein suggesting that the already dysfunctional neurons were additionally stressed by the SARS-CoV2 induced microangiopathy. ACE2+ human brain endothelial cells treated with high dose (but not vaccine equivalent low dose) spike S1 protein demonstrated each of the molecular changes noted in the in vivo COVID-19 and COVID-19/Alzheimer's disease brain tissues. It is concluded that fatal COVID-19 induces a diffuse microencephalitis and microglial activation in the brain due to endocytosis of circulating viral spike protein that amplifies pre-existing dementia in at least two ways: 1) modulates the expression of proteins that may worsen Alzheimer's disease and 2) stresses the already dysfunctional neurons by causing an acute proinflammatory/hypercoagulable/hypoxic microenvironment in areas with abundant hyperphosphorylated tau protein and/or βA-42.
预先存在的阿尔茨海默病是 COVID-19 严重/致命病例的一个风险因素，而 SARS-CoV2 病毒的感染与未掩盖的阿尔茨海默病发病率增加有关。SARS-CoV2 可能放大阿尔茨海默病的分子基础尚不清楚。本研究分析了死于 COVID-19 的预先存在痴呆症患者（n=5）的尸检脑组织中的分子变化，并与死于 COVID-19 但无痴呆症病史的患者（n=8）、COVID-19 前的阿尔茨海默病患者（n=10）和年龄匹配的对照组（n=10）的等效组织进行了盲法比较。免疫组织化学分析证实了 COVID-19 组中 4 例阿尔茨海默病（n=4）和 1 例路易体痴呆（n=1）的诊断。无痴呆症病史的 COVID-19 患者的脑组织表现出弥漫性微血管病，其特征是主要由 CD31+内皮细胞内化尖峰亚单位 S1 和 S2，强烈与 ACE2、Caspase-3、IL6、TNFα 和补体成分 6 共定位，这与 SARS-CoV2 RNA 无关。以 TMEM119 和 MCP1 蛋白表达增加为特征的小胶质细胞激活与内化的尖峰蛋白密切平行。与对照组相比，无预先存在痴呆症的 COVID-19 患者的组织中神经元型一氧化氮合酶和 NMDAR2 的表达增加了 5-10 倍，并且与阿尔茨海默病恶化相关的蛋白质表达显著下降：MFSD2a、SHIP1、BCL6、BCL10 和 BACH1。在痴呆症患者的 COVID-19 组织中，广泛的尖峰诱导的微小脑炎与同时发生的小胶质细胞激活共存于神经元具有过度磷酸化 tau 蛋白的相同区域，这表明已经功能失调的神经元被 SARS-CoV2 诱导的微血管病进一步应激。用高剂量（而非疫苗等效低剂量）尖峰 S1 蛋白处理的 ACE2+人脑内皮细胞表现出体内 COVID-19 和 COVID-19/阿尔茨海默病脑组织中观察到的每种分子变化。结论是，致命的 COVID-19 由于循环病毒尖峰蛋白的内吞作用而在大脑中引起弥漫性微小脑炎和小胶质细胞激活，至少以两种方式放大预先存在的痴呆症：1）调节可能加重阿尔茨海默病的蛋白质的表达，2）通过在富含过度磷酸化 tau 蛋白和/或βA-42 的区域引起急性促炎/高凝/缺氧的微环境来使已经功能失调的神经元紧张。
