A hallmark pathology of Alzheimer's disease (AD) is the formation of amyloid β (Aβ) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aβ morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of Aβ peptides, the levels and length of Aβ that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of Aβ morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aβ deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of Aβ deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aβ40 and Aβ42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse Aβ42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aβ42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of Aβ pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aβ pathology in the Alzheimer's cascade.

中文翻译：

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阿尔茨海默型淀粉样变性模型中 Aβ 沉积形态和次级蛋白质组不溶性的多样性。


阿尔茨海默氏病 (AD) 的一个标志性病理学是β淀粉样蛋白 (Aβ) 沉积物的形成，其表现出不同的定位和形态，从脑实质中的弥漫性沉积物到核心神经炎沉积物，以及软脑膜和实质室中的脑血管沉积物。大多数 AD 大脑表现出全谱的病理 Aβ 形态。在 AD 淀粉样变性模型研究过程中，我们生成了多种转基因小鼠模型，这些模型的表达转基因结构的性质各不相同；包括 Aβ 肽的物种起源、沉积的 Aβ 水平和长度，以及突变早老素 1 (PS1) 是否共表达。这些模型概括了人类 AD 淀粉样变性的特征，但有趣的是，一些模型可以产生以一种 Aβ 形态占主导地位的病理学。在先前对主要产生核心神经炎沉积物的小鼠的研究中，我们确定 Aβ 沉积与胞浆蛋白溶解度的变化有关，其中一部分蛋白质变得不溶于去污剂，表明次级蛋白质组不稳定。在这里，我们调查了七种不同的转基因小鼠模型中胞浆蛋白溶解度的变化，这些模型表现出一系列 Aβ 沉积形态。我们发现这些模型中蛋白质组溶解度的变化范围令人惊讶。将人类 Aβ40 和 Aβ42 沉积在核心神经炎斑块中的小鼠的蛋白质组溶解度变化最为明显。在小鼠大脑中也检测到了不溶性胞质蛋白，这些蛋白形成了弥漫性 Aβ42 沉积物，但程度较小。值得注意的是，具有仅含有 Aβ42 的核心沉积物的小鼠具有相对较少的不溶于洗涤剂的蛋白质。 我们的数据提供了对不同类型 Aβ 病理所导致的生物效应多样性的新见解，并支持纤维状核心神经炎斑块病理是阿尔茨海默病级联中更具破坏性的 Aβ 病理的观点。