Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimer's dementias.
Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimer's dementias.
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DOI：
10.1111/jnc.15694
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发表时间：
2022-11
影响因子：
4.7
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中科院分区：
文献类型：
--
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家族性英国痴呆（FBD）和家族性丹麦痴呆（FDD）是常染色体显性痴呆，由整体膜蛋白2B （ITM2B，也称为BRI2）基因突变引起。突变体BRI2的分泌酶加工导致BRI2衍生的淀粉样蛋白肽、ABri和ADan的分泌和沉积，类似于APP/β -淀粉样蛋白（Aβ）病理，这是阿尔茨海默病（AD）的特征。FBD/FDD的淀粉样蛋白病理主要表现在微血管中，ABri/ADan含有脑淀粉样血管病（CAA）。虽然ABri和ADan肽序列仅在少数C端氨基酸上有所不同，但FDD中的CAA以ADan与a β共聚集为特征，而FBD中没有观察到a β沉积。事实上，FDD患者比FBD患者表现出更早和更严重的疾病发病，这表明与FBD相比，ADan和a β共聚集的潜在作用促进了FDD患者更快的疾病进展。因此，描述这两种血管性痴呆中淀粉样蛋白聚集的化学特征是至关重要的。这反过来又将增加对这些疾病的病理生理学和异质性淀粉样肽相互作用和沉积的致病作用的知识。在此，我们使用基质辅助激光解吸/电离质谱成像（MALDI - MSI）结合基于发光共轭寡硫吩探针（LCO）的高光谱共聚焦显微镜，描绘了FBD、FDD患者死后脑组织中单个CAA的结构特征和相关的淀粉样肽模式，以及无AD的散发性CAA (CAA+)，显示明显的CAA，无实质斑块。结果表明，FBD和FDD中的CAA均由N端截断和焦谷氨酸修饰的淀粉样肽（ADan和ABri）组成，但与FBD中的ABri相比，FDD中的ADan肽也被广泛的C端截断，这有助于ADan的疏水性。此外，FDD中的CAA与Aβ x - 42和Aβ x - 40共沉积。CAA+血管在结构上比FDD/FBD CAA更成熟，并且含有大量的焦谷氨酸Aβ。与FDD相比，CAA+中的Aβ表现出更多的C端截断和更少的N端截断。在FDD中，ADan与Aβ3pE‐40和Aβ3‐40存在空间共定位，但与Aβx‐42不存在空间共定位。这表明FDD中Aβ的聚集倾向增加，促进了Aβ和ADan的共聚集。此外，CAA成熟度似乎主要受Aβ含量的影响，CAA+的500/580模式明显高于FDD和FBD。这是同类研究中首次全面描述FDD/FBD和散发性CAA中单个血管斑块中Bri2和APP衍生的淀粉样蛋白肽，为非AD相关的血管淀粉样蛋白病理提供了新的见解。MALDI质谱成像是一种新的生化成像技术，用于阐明家族性英国和丹麦痴呆（FBD/FDD）血管沉积物中淀粉样肽种类的不同聚集模式。本期封面图片：https://doi.org/10.1111/jnc.15424
Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2‐derived amyloidogenic peptides, ABri and ADan that resemble APP/β‐amyloid (Aβ) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA). While ABri and ADan peptide sequences differ only in a few C‐terminal amino acids, CAA in FDD is characterized by co‐aggregation of ADan with Aβ, while in contrast no Aβ deposition is observed in FBD. The fact that FDD patients display an earlier and more severe disease onset than FBD suggests a potential role of ADan and Aβ co‐aggregation that promotes a more rapid disease progression in FDD compared to FBD. It is therefore critical to delineate the chemical signatures of amyloid aggregation in these two vascular dementias. This in turn will increase the knowledge on the pathophysiology of these diseases and the pathogenic role of heterogenous amyloid peptide interactions and deposition, respectively. Herein, we used matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) in combination with hyperspectral, confocal microscopy based on luminescent conjugated oligothiophene probes (LCO) to delineate the structural traits and associated amyloid peptide patterns of single CAA in postmortem brain tissue of patients with FBD, FDD as well as sporadic CAA without AD (CAA+) that show pronounced CAA without parenchymal plaques. The results show that CAA in both FBD and FDD consist of N‐terminally truncated‐ and pyroglutamate‐modified amyloid peptide species (ADan and ABri), but that ADan peptides in FDD are also extensively C‐terminally truncated as compared to ABri in FBD, which contributes to hydrophobicity of ADan species. Further, CAA in FDD showed co‐deposition with Aβ x‐42 and Aβ x‐40 species. CAA+ vessels were structurally more mature than FDD/FBD CAA and contained significant amounts of pyroglutamated Aβ. When compared with FDD, Aβ in CAA+ showed more C‐terminal and less N‐terminally truncations. In FDD, ADan showed spatial co‐localization with Aβ3pE‐40 and Aβ3‐40 but not with Aβx‐42 species. This suggests an increased aggregation propensity of Aβ in FDD that promotes co‐aggregation of both Aβ and ADan. Further, CAA maturity appears to be mainly governed by Aβ content based on the significantly higher 500/580 patterns observed in CAA+ than in FDD and FBD, respectively. Together this is the first study of its kind on comprehensive delineation of Bri2 and APP‐derived amyloid peptides in single vascular plaques in both FDD/FBD and sporadic CAA that provides new insight in non‐AD‐related vascular amyloid pathology. Cover Image for this issue: https://doi.org/10.1111/jnc.15424 MALDI mass spectrometry imaging, a novel biochemical imaging technique, was used to elucidate the differential aggregation pattern of amyloid peptide species in vascular deposits in familial British and Danish dementia (FBD/FDD). Cover Image for this issue: https://doi.org/10.1111/jnc.15424
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影响因子：
7.4
作者：
Michno, Wojciech;Kaya, Ibrahim;Hanrieder, Jorg
通讯作者：
Hanrieder, Jorg
影响因子：
4.7
作者：
Michno, Wojciech;Wehrli, Patrick;Hanrieder, Jorg
通讯作者：
Hanrieder, Jorg
散发性和遗传性脑淀粉样血管病的遗传学和分子发病机制。
影响因子：
12.7
作者：
Revesz T;Holton JL;Lashley T;Plant G;Frangione B;Rostagno A;Ghiso J
通讯作者：
Ghiso J
DOI：
10.1136/jnnp-2016-314697
发表时间：
2017-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Banerjee G;Carare R;Cordonnier C;Greenberg SM;Schneider JA;Smith EE;Buchem MV;Grond JV;Verbeek MM;Werring DJ
通讯作者：
Werring DJ
影响因子：
4
作者：
Nystrom, Sofie;Psonka-Antonczyk, Katarzyna M.;Nilsson, K. Peter R.
通讯作者：
Nilsson, K. Peter R.