唐氏综合征中 APP 基因剂量增加的影响及 Dp16 小鼠模型。
Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.
机构信息
Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.
出版信息
Alzheimers Dement. 2022 Jun;18(6):1203-1234. doi: 10.1002/alz.12463. Epub 2021 Nov 10.
Abstract
INTRODUCTION
People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. In AD-DS, but not sporadic AD, increased APP copy number is necessary, defining the APP gene dose hypothesis. Which amyloid precursor protein (APP) products contribute needs to be determined.
METHODS
Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (Aβ) peptides were measured in DS, AD-DS, non-demented controls (ND), and sporadic AD cases. The APP gene-dose hypothesis was evaluated in the Dp16 model.
RESULTS
DS and AD-DS differed from ND and AD for all APP products. In AD-DS, Aβ42 and Aβ40 levels exceeded AD. APP products were increased in the Dp16 model; increased APP gene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia.
DISCUSSION
Increases in APP products other than Aβ distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering which APP products contribute and how.
摘要
简介
唐氏综合征（DS）患者易患阿尔茨海默病（AD）。淀粉样蛋白假说为 AD 研究提供了信息。在 AD-DS 中，但不在散发性 AD 中，增加 APP 拷贝数是必需的，这定义了 APP 基因剂量假说。需要确定哪些淀粉样前体蛋白（APP）产物有贡献。
方法
在 DS、AD-DS、非痴呆对照（ND）和散发性 AD 病例中测量全长蛋白（fl-hAPP）、C 端片段（hCTFs）和淀粉样β（Aβ）肽的脑水平。在 Dp16 模型中评估了 APP 基因剂量假说。
结果
DS 和 AD-DS 与 ND 和 AD 相比，所有 APP 产物均有差异。在 AD-DS 中，Aβ42 和 Aβ40 水平超过 AD。Dp16 模型中增加了 APP 产物；增加 APP 基因剂量是易损神经元丧失、tau 病理和星形胶质细胞和小胶质细胞激活所必需的。
讨论
除了 Aβ之外，APP 产物的增加将 AD-DS 与 AD 区分开来。要阐明 AD-DS 的发病机制，就必须阐明哪些 APP 产物有贡献以及如何有贡献。
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