Aβ truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition.
Aβ truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition.
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DOI：
10.1016/j.bbadis.2017.07.005
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Ghiso J
中科院分区：
文献类型：
--
作者：
Cabrera E;Mathews P;Mezhericher E;Beach TG;Deng J;Neubert TA;Rostagno A;Ghiso J
广泛的实质和血管Aβ沉积是阿尔茨海默病(AD)的病理特征。除了经典的全长多肽，对脑沉积的生化分析显示，Aβ高度异质性可能是多种蛋白水解酶作用的结果。尽管许多研究集中在A-β，但N-端和C-端截短的物种与AD发病机制的相关性仍未得到很大程度的研究。在目前的工作中，使用新的抗体特异性识别在第4位N端截断或在第34位C端截断的Aβ物种，我们提供了一个清晰的评估这些物种在AD脑和转基因模型中的不同地形定位。根据其不同的溶解性，脑N-端和C-端截断物种通过差示分级提取，并通过免疫沉淀与质谱分析相结合的方法进行鉴定。合成同系物的生化/生物物理研究进一步证实了组成脑Aβ多肽的截断物种的不同溶解性和对比的纤维蛋白原特征。β的C末端降解会导致更多可溶性片段的产生，这些片段很可能更容易从大脑中消除。相反，位置4的N末端截断有利于形成具有高淀粉样蛋白生成倾向的难溶的、易于聚集的多肽，并有可能加剧纤维沉积，使淀粉样蛋白生成环自我延续。对在不同疾病阶段组成间质液体和淀粉样蛋白沉积的Aβ物种的分子多样性的详细评估，以及在各种药理学方法中对截断图谱的评估，将有助于全面理解Aβ截断在疾病发病机制中仍未确定的贡献及其作为新的治疗靶点的潜力。
Extensive parenchymal and vascular Aβ deposits are pathological hallmarks of Alzheimer’s disease (AD). Besides classic full-length peptides, biochemical analyses of brain deposits have revealed high degree of Aβ heterogeneity likely resulting from the action of multiple proteolytic enzymes. In spite of the numerous studies focusing in Aβ, the relevance of N- and C-terminal truncated species for AD pathogenesis remains largely understudied. In the present work, using novel antibodies specifically recognizing Aβ species N-terminally truncated at position 4 or C-terminally truncated at position 34, we provide a clear assessment of the differential topographic localization of these species in AD brains and transgenic models. Based on their distinct solubility, brain N- and C-terminal truncated species were extracted by differential fractionation and identified via immunoprecipitation coupled to mass spectrometry analysis. Biochemical/biophysical studies with synthetic homologues further confirmed the different solubility properties and contrasting fibrillogenic characteristics of the truncated species composing the brain Aβ peptidome. Aβ C-terminal degradation leads to the production of more soluble fragments likely to be more easily eliminated from the brain. On the contrary, N-terminal truncation at position 4 favors the formation of poorly soluble, aggregation prone peptides with high amyloidogenic propensity and the potential to exacerbate the fibrillar deposits, self-perpetuating the amyloidogenic loop. Detailed assessment of the molecular diversity of Aβ species composing interstitial fluid and amyloid deposits at different disease stages, as well as the evaluation of the truncation profile during various pharmacologic approaches will provide a comprehensive understanding of the still undefined contribution of Aβ truncations to the disease pathogenesis and their potential as novel therapeutic targets.
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影响因子：
12.7
作者：
Bouter Y;Dietrich K;Wittnam JL;Rezaei-Ghaleh N;Pillot T;Papot-Couturier S;Lefebvre T;Sprenger F;Wirths O;Zweckstetter M;Bayer TA
通讯作者：
Bayer TA
影响因子：
4
作者：
Bolognesi, Benedetta;Kumita, Janet R.;Yerbury, Justin J.
通讯作者：
Yerbury, Justin J.
影响因子：
4.8
作者：
Fossati, S.;Cam, J.;Rostagno, A.
通讯作者：
Rostagno, A.
影响因子：
82.9
作者：
Bateman, Randall J.;Munsell, Ling Y.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
2.9
作者：
He, WL;Barrow, CJ
通讯作者：
Barrow, CJ