Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
BioArctic AB, Stockholm, Sweden; Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
Neurosci Lett. 2021 May 29;754:135894. doi: 10.1016/j.neulet.2021.135894. Epub 2021 Apr 10.
The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
阿尔茨海默病（AD）的主要特征是淀粉样斑块，由聚集的β淀粉样蛋白（Aβ）肽组成，与tau 病理学（斑块周围的缠结、神经原纤维小径和变性神经突）一起存在于大脑中。唐氏综合征（DS）个体患 AD 型病理学的风险增加；大多数 DS 个体在 40 岁时已经发展出大量的病理学。DS 个体有额外的 21 号染色体拷贝，携带淀粉样前体蛋白基因（APP）。我们的目的是研究 DS 和 AD 大脑中的 Aβ 肽模式，以分别研究其淀粉样沉积和聚集的差异。从患有 DS（具有淀粉样病理学）的患者、散发性 AD 和对照的皮质组织中匀浆并分成 TBS（水溶性）和甲酸（水不溶性）部分。使用针对不同 Aβ 物种的各种抗体（包括寡聚体 Aβ）进行免疫沉淀（IP）。然后使用质谱法评估不同患者组中 Aβ 物种的存在。鉴定出大量 Aβ 肽，包括 Aβ1-X、2-X、3-X、4-X、5-X、11-X 和 Aβ 肽，其延伸到 BACE1 切割位点的 N 端并在 Aβ 序列 APP/Aβ 中结束-X 至 15），以及通过焦谷氨酸形成进行翻译后修饰的肽。与对照相比，大多数 Aβ 肽在 AD 和 DS 中丰度较高，除了 APP/Aβ（-X 至 15）肽，在 DS 中丰度最高，其次是对照和 AD。此外，与 AD 相比，DS 中 AβX-40 和 AβX-34 的丰度增加。Aβ1-40、Aβ1-42 和 Aβ4-42 被鉴定为原纤维的主要成分（使用 mAb158 进行 IP），与使用 6E10+4G8 进行 IP 的样品相比，获得了更高的相对 Aβ1-42 信号，表明原纤维/寡聚物富含在氨基酸 42 结束的肽。在 AD 中发现的所有 Aβ 肽也存在于 DS 中，表明 Aβ 肽产生、降解和积累的途径相似，除了 APP/Aβ（-X 至 15）。同样，在 AD 和 DS 中形成原纤维/寡聚物的 Aβ 肽相似，这意味着在散发性 AD 中具有临床益处的治疗也可能对 DS 患者有益。
