Takahashi Reisuke H, Yokotsuka Mayumi, Tobiume Minoru, Sato Yuko, Hasegawa Hideki, Nagao Toshitaka, Gouras Gunnar K
Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan.
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Brain Pathol. 2021 Sep;31(5):e12941. doi: 10.1111/bpa.12941. Epub 2021 Feb 23.
Alzheimer's disease (AD) is the main cause of dementia, and β-amyloid (Aβ) is a central factor in the initiation and progression of the disease. Different forms of Aβ have been identified as monomers, oligomers, and amyloid fibrils. Many proteins have been implicated as putative receptors of respective forms of Aβ. Distinct forms of Aβ oligomers are considered to be neurotoxic species that trigger the pathophysiology of AD. It was reported that cellular prion protein (PrP ) is one of the most selective and high-affinity binding partners of Aβ oligomers. The interaction of Aβ oligomers with PrP is important to synaptic dysfunction and loss. The binding of Aβ oligomers to PrP has mostly been studied with synthetic peptides, cell culture, and murine models of AD by biochemical and biological methods. However, the molecular mechanisms underlying the relationship between Aβ oligomers and PrP remain unclear, especially in the human brain. We immunohistochemically investigated the relationship between Aβ oligomers and PrP in human brain tissue with and without amyloid pathology. We histologically demonstrate that PrP accumulates with aging in human brain tissue even prior to AD mainly within diffuse-type amyloid plaques, which are composed of more soluble Aβ oligomers without stacked β-sheet fibril structures. Our results suggest that PrP accumulating plaques are associated with more soluble Aβ oligomers, and appear even prior to AD. The investigation of PrP accumulating plaques may provide new insights into AD.
阿尔茨海默病（AD）是痴呆的主要病因，β-淀粉样蛋白（Aβ）是该疾病发生和发展的核心因素。已鉴定出不同形式的Aβ，包括单体、寡聚体和淀粉样纤维。许多蛋白质被认为是各自形式Aβ的假定受体。不同形式的Aβ寡聚体被认为是引发AD病理生理的神经毒性物质。据报道，细胞朊蛋白（PrP）是Aβ寡聚体最具选择性和高亲和力的结合伙伴之一。Aβ寡聚体与PrP的相互作用对突触功能障碍和丧失很重要。Aβ寡聚体与PrP的结合大多通过生化和生物学方法，利用合成肽、细胞培养和AD小鼠模型进行研究。然而，Aβ寡聚体与PrP之间关系的分子机制仍不清楚，尤其是在人类大脑中。我们通过免疫组织化学方法研究了有或没有淀粉样病理的人类脑组织中Aβ寡聚体与PrP之间的关系。我们从组织学上证明，即使在AD之前，PrP也会随着年龄增长在人类脑组织中积累，主要在弥漫型淀粉样斑块内，这些斑块由更易溶的Aβ寡聚体组成，没有堆叠的β-折叠纤维结构。我们的结果表明，PrP积累斑块与更易溶的Aβ寡聚体有关，甚至在AD之前就出现。对PrP积累斑块的研究可能为AD提供新的见解。
