Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, APHP, Hôpital de La Pitié Salpêtrière, InsermParis, France.
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Acta Neuropathol. 2024 Jul 18;148(1):8. doi: 10.1007/s00401-024-02756-4.
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.
阿尔茨海默病（AD）的特征是细胞外含有淀粉样β（Aβ）肽的淀粉样斑块、神经元内神经原纤维缠结、细胞外神经丝和围绕由高度磷酸化的 tau 蛋白（pTau）组成的斑块的支化神经突。Aβ也可以在血管壁中沉积，导致脑淀粉样血管病（CAA）。虽然 AD 大脑中的淀粉样斑块是恒定的，但 CAA 在病例之间存在差异。本研究重点关注 APP 重复（APPdup）和唐氏综合征（DS）等罕见且研究较少的患者群体之间观察到的差异，这些患者群体报告称 CAA 水平升高的频率高于散发性 AD（sAD）、大多数 APP 突变和对照。我们比较了病例之间和使用质谱法（MS）的 Aβ 和 tau 病理学。我们进一步使用 MS-脑成像来描述 Aβ 肽的空间分布。虽然 sAD、AD 合并 DS（DS-AD）和 APP 突变合并 AD 中的脑实质内 Aβ 沉积数量众多，但在 APPdup 中则较少。相反，在 APPdup 和 DS-AD 中，血管内的 Aβ 沉积丰富，而仅在 APPdup 病例中，毛细血管内显示出高 Aβ 沉积。对 Aβ 肽谱的研究表明，APPdup 病例中 Aβx-37、Aβx-38 和 Aβx-40 的特异性增加，而 Aβx-42 则没有增加，DS-AD 病例的增加程度较低。有趣的是，与所有其他组相比，APPdup 中特别增加了 N 截断的 Aβ2-x 肽。APPdup 病例的软脑膜和脑实质血管的 MS-成像证实了这一结果，表明 CAA 与血管中 N-和 C-末端截断的较短 Aβ 肽的积累有关。总之，这项研究在 AD 病例之间，特别是在携带 APP 基因三个基因组拷贝的 APPdup 和 DS-AD 病例之间，确定了 Aβ 沉积的定位和组成存在显著差异。在这些患者的 CSF 或血浆中检测到特定的 Aβ 肽可能会改善 CAA 的诊断，并将其纳入抗淀粉样免疫治疗。
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