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.

阿尔茨海默氏病 (AD) 的特征是含有淀粉样蛋白-β (Aβ) 肽的细胞外淀粉样蛋白斑、神经元内神经原纤维缠结、细胞外神经毡线以及由过度磷酸化 tau 蛋白 (pTau) 组成的斑块周围的营养不良神经突。 Aβ 还可沉积在血管壁中，导致脑淀粉样血管病 (CAA)。虽然 AD 大脑中的淀粉样斑块是恒定的，但 CAA 因病例而异。该研究重点关注罕见和研究不足的APP重复 ( APP dup) 和唐氏综合症 (DS) 患者群体之间观察到的差异，据报道，与散发性 AD (sAD)、大多数APP突变和唐氏综合症 (DS) 相比，CAA 水平升高的频率更高。控制。我们使用质谱 (MS) 比较了不同病例死后脑组织中的 Aβ 和 tau 病理学以及 Aβ 肽。我们通过 MS 脑成像进一步表征了 Aβ 肽的空间分布。虽然 sAD、DS 伴 AD (DS-AD) 和 AD 伴APP突变中实质内 Aβ 沉积较多，但APP dup 中的 Aβ 沉积较少。相反， APP dup 和 DS-AD 中血管中 Aβ 沉积丰富，而只有APP dup 病例在毛细血管中显示出大量 Aβ 沉积。 Aβ 肽谱的研究显示，在APP dup 病例中，Aβx-37、Aβx-38 和 Aβx-40 特异性增加，但 Aβx-42 没有增加，而在 DS-AD 病例中，Aβx-42 的增加程度较低。有趣的是，与所有其他组相比， APP dup 中 N-截短的 Aβ2-x 肽尤其增加。 这一结果得到了APP dup 病例的软脑膜和实质血管 MS 成像的证实，表明 CAA 与血管中 N 端和 C 端截短的较短 Aβ 肽的积累有关。总而言之，这项研究发现 AD 病例之间 Aβ 沉积物的定位和组成存在显着差异，特别是APP dup 和 DS-AD，两者都携带APP基因的三个基因组拷贝。检测这些患者的脑脊液或血浆中的特定 Aβ 肽可以改善 CAA 的诊断并将其纳入抗淀粉样蛋白免疫治疗中。