Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department of Clinical Neuroscience & Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Brain Pathol. 2021 Sep;31(5):e12952. doi: 10.1111/bpa.12952. Epub 2021 Mar 22.
Prion-like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α-synuclein (α-syn) deposits has been reported in the brains of animal models injected with synthetic α-syn fibrils or pathological α-syn prepared from patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, α-syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α-syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α-syn pathology in the brain using α-syn epitope-specific antibodies, antiphosphorylated α-syn antibodies (pSyn#64 and pSer129), anti-ubiquitin antibodies, and anti-p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α-syn epitope-specific antibodies revealed Lewy bodies, massive α-syn-positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human-specific α-syn antibody targeting amino acid residues 115-122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α-syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α-syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α-syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α-syn pathology is limited.
朊病毒样异常蛋白的传播被认为发生在神经退行性疾病中，并且已经在注射合成的α-突触核蛋白 (α-syn) 纤维或来自帕金森病 (PD) 和路易体痴呆 (DLB) 患者的病理性α-syn 的动物模型的大脑中报告了α-syn 沉积物的进展。然而，在与人类更相似的非人类灵长类动物中，α-syn 的传播尚未完全阐明。在这里，我们将合成的人类α-syn 纤维注入猕猴（Macaca fuscata）的左侧纹状体。在注射后 3 个月，我们使用α-syn 表位特异性抗体、磷酸化α-syn 抗体（pSyn#64 和 pSer129）、抗泛素抗体和抗 p62 抗体检查大脑中的神经退行性变和α-syn 病理学。用 pSyn#64、pSer129 和α-syn 表位特异性抗体进行免疫组织化学检查显示出路易体、大量α-syn 阳性神经元细胞内包涵体（NCIs）和神经突在左侧壳核中。这些包涵体也对泛素和 p62 呈阳性。LB509 是一种针对氨基酸残基 115-122 的人类特异性α-syn 抗体，在注射部位周围显示出有限的免疫反应性。左侧黑质（SN）和双侧额叶皮质也含有一些 NCIs 和神经突。包括顶叶/颞叶皮质在内的左侧大脑半球表现出稀疏的α-syn 病理学，嗅神经、杏仁核、海马体或右侧顶叶/颞叶皮质均未见免疫反应性。除了左侧纹状体和 SN 外，具有α-syn 病理学的区域中的神经元丢失和神经胶质增生均较轻。我们的结果表明，异常的α-syn 纤维通过投射、联合和连合纤维在猕猴的大脑中传播，尽管α-syn 病理学的进展是有限的。
