BACE2

更新于：2025-05-07

基本信息

别名

AEPLC、ALP56、Asp 1

+ [16]

简介

Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672 (PubMed:10591213, PubMed:11083922, PubMed:11423558, PubMed:15857888, PubMed:16816112). Involved in the proteolytic shedding of PMEL at early stages of melanosome biogenesis. Cleaves PMEL within the M-beta fragment to release the amyloidogenic PMEL luminal fragment containing M-alpha and a small portion of M-beta N-terminus. This is a prerequisite step for subsequent processing and assembly of PMEL fibrils into amyloid sheets (PubMed:23754390). Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells (PubMed:21907142).

关联

100 项与 BACE2 相关的临床结果

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100 项与 BACE2 相关的转化医学

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0 项与 BACE2 相关的专利（医药）

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552

项与 BACE2 相关的文献（医药）

2025-05-01·Protein science : a publication of the Protein Society

Molecular mechanisms of RaTG13 and SARS-CoV-2 RBD bound to Rhinolophus affinis bat ACE2.

Article

作者: Lan, Jun ; Fan, Shilong ; Li, Min ; Wang, Chenghai ; Deng, Yang ; Nan, Xiaoyan

The discovery of the RaTG13 coronavirus in Rhinolophus affinis bats in 2013, sharing 96.3% genome homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggested bats as the origin of SARS-CoV-2. Although both human angiotensin-converting enzyme 2 (hACE2) and Rhinolophus affinis bat ACE2 (bACE2-Ra, seven polymorphic variants named 01-07) are known to serve as entry receptors for these coronaviruses, the binding mechanism of RaTG13 receptor binding domain (RBD) bound to bACE2-Ra remains poorly understood. Here, we found that RaTG13 RBD bound to bACE2-Ra-07 with a weaker affinity (2.42 μM) compared with SARS-CoV-2 RBD (372 nM). Additional glycosylation at residue N370 of RaTG13 had little influence on bACE2-Ra-07 binding by RaTG13 RBD. Crystal structures of the SARS-CoV-2 and RaTG13 N370Q RBD bound to bACE2-Ra-07 were solved. Interface analysis and surface plasmon resonance (SPR) assay indicated that residue substitutions at 493, 498, 501, and 505 may play a more important role in the cross-species recognition of bACE2-Ra-07 by the SARS-CoV-2 RBD. Besides, the N370Q mutation enhanced the binding affinity between the RBD of pangolin coronavirus isolated from Guangxi (PCoV-GX) and the bACE2-Ra-07 receptor by over 10-fold. Furthermore, the recently prevalent SARS-CoV-2 variant RBDs extensively retained the interaction with the bACE2-Ra-07 receptor. Our findings give new lights on the cross-species evolution of SARS-CoV-2 and prompt the urgency to monitor the circulation of coronaviruses in bats to better prevent future spillover.

2025-04-16·ACS Chemical Neuroscience

Uncovering Amyloid-β Interactions: Gray versus White Matter

Article

作者: Cathoud, Gabriel ; Lyubchenko, Yuri ; Simões, Pedro ; Hashemi, Mohtadin

Alzheimer's disease is characterized by the accumulation of amyloid plaques in the brain. Recent studies suggest that amyloid-β (Aβ) peptides interact with cell membranes, potentially catalyzing plaque formation. However, the effect of varying cell membrane compositions on this catalytic process requires further investigation. Using molecular dynamics simulations, we demonstrate that a model gray matter membrane significantly influences the secondary structure of β-amyloid peptides. Notably, residues Asp1 and Glu22 play crucial roles in the membrane interaction. Glutamic acid at position 22, located in the middle of the peptide chain, appears to promote the formation of β-hairpin conformations, which are critical for aggregation. Additionally, our simulations reveal that the model white matter membrane allows a spontaneous insertion of segments of the peptide into the membrane, suggesting that membrane interaction not only alters the peptide structure but may also compromise membrane integrity. Our results show that the different membrane compositions in the brain may play different roles when interacting with β-amyloid peptides.

2025-04-01·Plant Physiology and Biochemistry

Integrated transcriptome and metabolome analysis revealed hub genes and metabolites associated with subzero temperature tolerance following cold acclimation in rapeseed (Brassica rapa L.)

Article

作者: Fahim, Abbas Muhammad ; Rahman, Faiz Ur ; Li, Ma ; Gang, Yang ; Nie, Zhixing ; Mumtaz, Muhammad Zahid ; Wangtian, Wang ; Wancang, Sun ; Yuanyuan, Pu ; Junyan, Wu ; Cao, Liru

Rapeseed naturally endures low temperature in late autumn and early winter to develop cold adaptation, named as cold acclimation (CA). The underlying mechanism by which CA induces plant resistance to subzero temperature tolerance is unclear. This study examined the transcriptome and metabolome of strong (Longyou 7) and weak (Longyou 99) cold-tolerant rapeseed varieties treated with treatments CA and sub-zero temperatures at fourth leaf stage. Cold shock (CS) treatment was developed by incubating seedlings directly at 0, -3, and -7 °C for 4 day at each temperature. For CA, seedlings were acclimatized at 4 °C for one week and then to 0, -3, and -7 °C for four days in each temperature. By transcriptome analysis 5364 and 6534 DEGs were detected in both varieties following CA. Functional enrichment analysis of DEGs showed that carbohydrate metabolism and biosynthesis of secondary metabolic pathways were enriched following CA. A weighted gene co-expression network analysis revealed hub genes AMY2, DREB, MYB, PBL, and GFT1 from three biological modules that can be employed as candidate genes to investigate the network regulation pathway of rapeseed in response to CA treatment. Metabolome profiling revealed phenylalanine, purine, amino sugar and nucleotide sugar, and flavonoid biosynthesis were the most enriched pathways in rapeseed seedlings following CA. Contemporaneous analysis of transcriptomics and metabolomic changes following CA revealed the dynamics of specific gene-metabolite relationships in rapeseed. DEGs and DAMs correlation analysis showed that genes DREB, RAP, TCP2, ZAT12, ASP1, ASP3, ASP4, and the metabolites N-acetyl-D-glucosamine, 2-glycitein, and 3-hydroxybenzyl alcohol glucoside, played an important role in rapeseed following CA. This study's findings elucidate the molecular and regulatory mechanisms enabling rapeseed to withstand subzero temperatures following CA.

项与 BACE2 相关的新闻（医药）

2023-07-16

·生物制药小编

Aβ假说40年一结果，有褒有贬…

1984年，β淀粉样斑块（Aβ）被确认为阿尔兹海默病（AD）细胞外淀粉样斑块的主要成分，也是AD的独特病理标志。随后，与1992年人们又提出的“淀粉样蛋白级联假说”认为大脑中Aβ沉积是AD发病机制。2023年7月6日，由渤健（Biogen）/卫材（Eisai）开发的Leqembi（Lcanemab）获FDA完全批准上市。历经40年的努力，人们又艰难地向前迈出一步。哪怕对此结果有褒有贬！Signal Transduct Target Ther. 2023 Jun 30;8(1):248. Leqembi与前车Leqembi早先就于2023年1月获FDA加速批准，这次完全批准基于Ⅲ期临床试验（NCT03887455）数据：治疗后6个月开始认知功能下降速度放缓，主要终点18个月时临床痴呆评分总和（CDR-SB1）下降了27%，其他所有的关键次要终点也具有显著性结果。数据这是渤健/卫材联合开发的第二款Aβ抗体。第一款是Aduhelm，于2021年6月7日获FDA批准上市。但同年7月又收到了缩小使用人群的决定，将适应症修改为轻症AD患者。2022年3月，卫材宣布不再与渤健分享Aduhelm销售利润并承担共同损失，渤健将独立负责Aduhelm开发决策和商业化，3月30日渤健向FDA提交了4期试验的方案。2022年4月渤健宣布将保留最少资源管理4期试验。在经历坎坷命运后，Aduhelm几乎被完全放弃。两款药虽同为Aβ抗体，但早先的研究中已发现各具不同结合特点，也因此造成不同结局。机制生理状态下，非淀粉样蛋白生成途径占主导，阻止Aβ产生。在淀粉样蛋白生成途径中：β-分泌酶首先在Asp1位点切割APP，产生sAPPβ和C99，随后γ-分泌酶裂解C99，释放Aβ和CTFγ。经过β-分泌酶、γ-分泌酶先后两次切割后产生Aβ。Signal Transduct Target Ther. 2023 Jun 30;8(1):248. 产生的Aβ单体聚集成为Aβ寡聚体（AβO）、Aβ原纤维（protofibrils）、Aβ纤维高聚集体（fibrils）等多种形式，并可改变构象成为斑块，通过多种机制介导AD疾病。Signal Transduct Target Ther. 2023 Jun 30;8(1):248. Aβ致病机制描述破坏膜结构Aβ与膜结合破坏膜完整性，导致神经元死亡；膜还为Aβ合成提供原料。干扰突触可塑性AβO改变突触形态、密度，导致突触功能受损。诱导tau蛋白病Aβ通过tau导致神经元损伤、神经炎症；tau毒性状态促进Aβ产生。诱发炎症Aβ刺激胶质细胞产生促炎细胞因子，并使其对各类刺激敏感性增加。诱导线粒体功能障碍AβO破坏线粒体裂变--融合平衡，损伤神经元，并产生过量ROS促进Aβ形成。改变神经化学系统Aβ抑制谷氨酸摄取，刺激谷氨酸释放，使突触间隙谷氨酸水平升高，抑制兴奋性神经元。损害大脑网络功能连接减少。因此靶向清除Aβ是治疗AD的主要策略。Aduhelm和Leqembi两款药物都能够与Aβ聚合体结合，亲和种类不同。Aduhelm与已停止研发的Gantenerumab都是更倾向结合Aβ纤维高聚集体（fibrils）；而Leqembi与Aβ原纤维（protofibrils）的结合能力更强。Eisai官网在头对头比较中，Leqembi结合75-300kDa较小的原纤维（protofbrils）的强度是Aduhelm的100倍，结合300-500kDa较大原纤维（protofibrils）的强度是Aduhelm的25倍。因此通过结合Aβ原纤维可导致更多的Aβ斑块溶解。Neurotherapeutics 20, 195–206 (2023). 而且抗体结合血管壁沉积的Aβ纤维高聚集体（fibrils）后容易引起炎症和血管壁渗漏，导致淀粉样蛋白相关影像学异常（ARIA），是引起脑水肿重要原因。而Leqembi的不同于其他二者的结合特性也能带来更低的ARIA发生率。其他药物针对Aβ的形成过程，已有多种靶点的药物进入临床试验，但进展不是很快。大多Aβ靶向药物都缺乏特异性和准确性转化模型，在研发过程中以失败告终，缩小基础研究和临床之间的差距还需要继续努力。靶点名称作用机制研发阶段/上市Aβ单体ABBV-916识别N3处截断的Aβ。2ABVac 40针对Aβ40的C端。2AV-1959DDNA疫苗，融合Aβ1-11至12三个靠背的编码序列，以产生Aβ抗体2Donanemab人源化IgG1单抗，针对Aβ焦谷氨酸形式，抑制聚集。3MEDI1814针对Aβ42 C端的特异性抗体。nPRX012人源化IgG1单抗，针对Aβ N端，刺激小胶质细胞的吞噬作用。nRemternetug单抗，识别N3焦谷氨酸修饰的截断Aβ，阻止聚集。1,3Solanezumab人源IgG1单抗，针对Aβ肽中部结构，减少Aβ诱导的突触毒性。2/3UB-311合成肽疫苗，中和Aβ毒性，促进斑块清除。nAβ聚合体ACI-24脂质体疫苗，引发针对Aβ的免疫反应。1,2ACU193人源化IgG2单抗，选择性结合Aβ寡聚物。1ALZ-101引起针对可溶性Aβ寡聚体的特异性免疫反应。1Grenezumab对寡聚体和纤维状Aβ高亲和，刺激对淀粉样斑块的吞噬作用。stopDNL919TREM2激动抗体，刺激小胶质细胞吞噬Aβ。1ICB-Ab002招募Treg、单核细胞吞噬Aβ并减轻炎症。1AduhelmIgG1单抗，针对Aβ N末端3-6位残基。phase4;21/6/7上市GantenerumabIgG1抗体，结合Aβ原纤维构象，招募小胶质细胞进行吞噬。stopTrontinemab新版的Gantenerumab，采用了罗氏（Roche）的“脑穿梭”技术，能够更好地越过BBB。1/2Lecanemab人源化IgG单抗，特异性结合大的Aβ原纤维。23/7/6上市Signal Transduct Target Ther. 2023 Jun 30;8(1):248. 小结靶向Aβ走的比较艰难。不过Leqembi的完全获批，为靶向抗Aβ的药物治疗和开发策略提供了很好的事实依据，也为疑虑“Aβ假说争议”的从业人员吃下一颗定心丸。无论主动免疫，还是被动免疫，阻止Aβ斑块形成将会在很长一段时间内是药物研发的重要方向。参考资料1Zhang Y et al. Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future. Signal Transduct Target Ther. 2023 Jun 30;8(1):248. 2.https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment3.https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval4.Biogen官网5.Eisai官网6.Söderberg, L. et al. Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer’s Disease. Neurotherapeutics 20, 195–206 (2023).

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