PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.
摘要：
阿尔茨海默病（AD）的特征是细胞外淀粉样蛋白斑块含有淀粉样蛋白-β（Aβ）肽，神经内神经原纤维缠结，细胞外神经纤维线，和围绕由过度磷酸化tau蛋白（pTau）组成的斑块的营养不良性神经突。Aβ还可以沉积在血管壁中,导致脑淀粉样血管病(CAA)。虽然AD大脑中的淀粉样蛋白斑块是恒定的，CAA因病例而异。该研究的重点是在APP重复（APPdup）和唐氏综合征（DS）的罕见和研究不足的患者组之间观察到的差异，据报道，与散发性AD（sAD）相比，其CAA水平升高的频率更高。大多数APP突变，和控制。我们使用质谱（MS）比较了死后脑组织中的Aβ和tau病理以及Aβ肽。我们用MS脑成像进一步表征了Aβ肽的空间分布。虽然sAD中实质内Aβ沉积众多，DS伴AD（DS-AD）和AD伴APP突变，这些在APPdup中不那么丰富。相反,APPdup和DS-AD中血管中的Aβ沉积物丰富，而只有APPdup病例在毛细血管中显示出高Aβ沉积物。对Aβ肽谱的调查显示，在APPdup病例中，Aβx-37，Aβx-38和Aβx-40有特定的增加，而在DS-AD病例中，Aβx-42没有增加。有趣的是,与所有其他组相比,N截短的Aβ2-x肽在APPdup中特别增加。通过APPdup病例的软脑膜和实质血管的MS成像证实了这一结果，提示CAA与血管中N-和C-末端截短的较短Aβ肽的积累有关。总之,这项研究确定了AD病例之间Aβ沉积物的位置和组成的显着差异，特别是应用和DS-AD，两者都携带APP基因的三个基因组拷贝。检测这些患者的CSF或血浆中的特异性Aβ肽可以改善CAA的诊断及其在抗淀粉样蛋白免疫疗法治疗中的纳入。
