Dominantly Inherited Alzheimer Network: Project 1

项目1：β淀粉样蛋白总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白（amyloid-β，Aβ）和神经元缠结为特征的疾病 由大脑中的tau蛋白组成。在淀粉样蛋白-β前体中已经鉴定出200多种突变 引起常染色体显性形式AD的蛋白质（APP）、早老素1（PSEN 1）和早老素2（PSEN 2） （ADAD）。PSEN 1和PSEN 2形成γ-分泌酶的催化结构域，该酶切割APP， 产生许多Aβ蛋白形式，这些蛋白形式可以被修饰成变体，包括翻译后修饰， 截短和序列变异。Aβ42/40亚型相对比值的变化已被用于 预测ADAD变体的致病性。然而，我们对其他Aβ蛋白形式的贡献知之甚少 AD发病机制和Aβ蛋白形式标签作为突变状态的生物标志物的效用，和/或 病程。例如，ADAD的Aβ致病原因是什么？几种Aβ蛋白形式支持 AD的因果作用，包括Aβ42、Aβ43、Aβ37、Aβ39和修饰，包括焦谷氨酸、氧化， 异构化和N-和C-末端截短。本研究的目的是确定ADAD的影响 突变和淀粉样变性对Aβ蛋白形式和疾病发病机制的影响。为了实现这一目标，我们将 使用新的质谱方法研究Aβ蛋白质型特征的突变和基因特异性效应， 人血浆、CSF、干细胞衍生的神经元和脑组织。然后我们将确定Aβ蛋白是如何 特征与人脑中组织学淀粉样蛋白斑块结构有关。我们假设ADAD突变 产生一种常见的致病性Aβ蛋白形式特征。提出这一建议的理由是， ADAD突变和淀粉样变性对Aβ蛋白形式的影响对于确定常见的致病性 导致AD的Aβ信号。这一目标验证将指导临床研究，治疗策略， 分类未来新的ADAD突变。这项工作将与遗传学， 生物标志物、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.