Dominantly Inherited Alzheimer Network: Project 1

项目1：淀粉样β蛋白摘要/摘要 阿尔茨海默病(AD)以淀粉样蛋白(Aβ，Aβ)堆积和神经原纤维缠结为特征 由大脑中的tau蛋白组成。已在淀粉样蛋白β前体中发现了200多个突变 导致常染色体显性AD的蛋白质(APP)、早老素1(PSEN1)和早老素2(PSEN2) (Adad)。PSEN1和PSEN2形成γ分泌酶的催化域，该酶将APP裂解成 产生许多Aβ蛋白形式，这些蛋白形式可以被修饰成包括翻译后修饰在内的变体， 截断和序列变异。β42/40亚型相对比例的变化已用于 预测ADAD变异体的致病性。然而，我们对其他Aβ蛋白形式的贡献知之甚少 AD发病机制及Aβ蛋白形态标志作为突变状态和/或生物标志物的应用 病程。例如，ADAD的Aβ致病原因(S)是什么？几种Aβ蛋白形式的支持 AD的因果作用，包括Aβ42，Aβ43，Aβ37，Aβ39和修饰，包括焦谷氨酸，氧化， 异构化，N-端和C-端截断。这项研究的目的是确定ADAD的影响 Aβ蛋白突变和淀粉样变性与疾病发病机制为了实现这一目标，我们将界定 用新的质谱学方法研究突变和基因特异性对β蛋白质组分的影响 人血浆、脑脊液、干细胞来源的神经元和脑组织。然后我们将确定β蛋白是如何形成的 信号与人脑中的组织学淀粉样斑块结构有关。我们假设ADAD突变 产生一种常见的致病Aβ蛋白样特征。这项提议的基本原理是，定义 ADAD突变和淀粉样变性对Aβ蛋白形式的影响将是确定常见致病因素的关键 导致AD的β签名。这一目标验证将指导临床研究、治疗策略和 对未来新的ADAD突变进行分类。这项工作将与Genetics合作进行， 生物标记物、临床、神经病理学、成像和生物统计学核心。

Project 1: Amyloid Beta SUMMARY/ABSTRACT Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and neurofibrillary tangles composed of the tau protein in the brain. More than 200 mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) that cause autosomal dominant forms of AD (ADAD). PSEN1 and PSEN2 form the catalytic domain of the γ-secretase enzyme, which cleaves APP to generate many Aβ proteoforms which can be modified into variants including posttranslational modifications, truncations and sequence variations. Changes in the relative ratios of Aβ42/40 isoforms have been used to predict pathogenicity of ADAD variants. However, we know less about the contribution of other Aβ proteoforms to AD pathogenesis and the utility of the Aβ proteoform signature as a biomarker of mutation status and/or disease course. For example, what are the Aβ pathogenic cause(s) of ADAD? Several Aβ proteoforms support a causal role for AD, including Aβ42, Aβ43, Aβ37, Aβ39 and modifications including pyroglutamate, oxidation, isomerization, and N- and C-terminal truncation. The objective of this study is to define the effects of ADAD mutations and amyloidosis on Aβ proteoform and disease pathogenesis. To meet this objective, we will define mutation and gene-specific effects on Aβ proteoform signatures using novel mass spectrometry approaches in human plasma, CSF, stem cell derived neurons, and brain tissue. We will then determine how Aβ proteoform signatures relate to histologic amyloid plaque structure in human brains. We hypothesize that ADAD mutations produce a common pathogenic Aβ proteoform signature. The rationale for this proposal is that defining the effects of ADAD mutations and amyloidosis on Aβ proteoforms will be critical to define the common pathogenic Aβ signatures which cause AD. This target validation will guide clinical studies, therapeutic strategies and classify future novel ADAD mutations. This work will be performed in collaboration with the Genetics, Biomarker, Clinical, Neuropathology, Imaging, and Biostatistics Cores.