预约演示

更新于：2025-01-23

ITM2B

更新于：2025-01-23

基本信息

别名

ABri23、BRI、BRI2

+ [19]

简介

Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites. Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42. Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.

关联

项与 ITM2B 相关的药物

WO2022218499

专利挖掘

靶点

ITM2B

作用机制-

在研机构

Alpha Beta Ltd.

原研机构

Alpha Beta Ltd.

在研适应症

痴呆

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ITM2B 相关的临床结果

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100 项与 ITM2B 相关的转化医学

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0 项与 ITM2B 相关的专利（医药）

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399

项与 ITM2B 相关的文献（医药）

2024-12-01·Alzheimer's & Dementia

Genetic Deletion of the Presinilin‐Like Peptidase SPPL2B Significantly Reduces Neuroinflammation and Halts Production and Plaque Deposition in Pre‐Clinical Models of Alzheimer’s Disease

Article

作者: Tambaro, Simone ; Garcia, Sandra Pérez ; Chen, Gefei ; Nilsson, Per ; Badman, Jack

AbstractBackgroundSignal Peptide Peptidase‐Like 2b (SPPL2b) is relevant for AD, being a brain‐specific intramembrane protein involved in the cleavage of Alzheimer’s disease (AD)‐related proteins, such as BRI2, inflammatory‐related proteins like CD74, TNFalpha, and Clec7a, and synaptic proteins Neuregulin‐1 and VAMP 1‐4. SPPL2b is specifically expressed in the hippocampus and cortex. The cleavage of TNFalpha by SPPL2b promotes the inflammatory pathway. Conversely, the SPPL2b substrate BRI2 regulates amyloid precursor protein (APP) cleavage and subsequent Aβ production. This work explores the pathophysiological role of SPPL2b in AD pathogenesis and investigates the potential of inhibiting SPPL2b activity as a novel therapeutic strategy.MethodTo characterize the role of SPPL2b in the APP cleavage process and neuroinflammation, we used neurons and glia primary cell cultures from WT and SPPL2b‐deficient mice. Furthermore, we assessed the therapeutic potential of inhibiting SPPL2b by employing a new AD mouse model generated through crossbreeding state‐of‐the‐art AppNL‐G‐F knock‐in mice with SPPL2b‐deficient mice. Cells and mouse brain samples were analyzed through western blotting, immunoprecipitation, and immunofluorescence. Aβ levels were quantified using ELISA kits.ResultThe results showed a significant increase in BRI2, followed by a substantial reduction in soluble APP, Aβ40, and Aβ42 levels in the conditioned media of SPPL2b KO neurons. Immunoprecipitation of BRI2 from the cortex of those mice revealed an increased interaction between BRI2 and APP in SPPL2b KO/AppNL‐G‐F mice. Most importantly, a notable decrease in brain Aβ plaque deposition and a significant decrease in both cortical and hippocampal gliosis were observed at 4 months‐of‐age in SPPL2b KO/AppNL‐G‐F mice.ConclusionThe results outlined in this study support a relevant connection between SPPL2b and the development of Aβ pathology in AD. In a global scenario characterized by the need to identify novel strategies to prevent and counteract AD progression, this study highlights and strengthens the importance of SPPL2b as a novel therapeutic approach for AD.

2024-10-28·Journal of Chemical Information and Modeling

Deciphering the Morphological Difference of Amyloid-β Fibrils in Familial and Sporadic Alzheimer’s Diseases

Article

作者: Ding, Feng ; Song, Zhiyuan ; Huang, Gangtong ; Xu, Yun ; Sun, Yunxiang

The aggregation of amyloid-β (Aβ) into amyloid fibrils is the major pathological hallmark of Alzheimer's disease (AD). Aβ fibrils can adopt a variety of morphologies, the relative populations of which are recently found to be associated with different AD subtypes such as familial and sporadic AD (fAD and sAD, respectively). The two AD subtypes differ in their ages of onset, AD-related genetic predispositions, and dominant Aβ fibril morphologies. We postulate that these disease subtype-dependent fibril morphology differences can be attributed to the intrinsic fibril properties and interacting molecules in the environment. Using atomistic discrete molecular dynamics simulations, we demonstrated that the fAD-dominant morphology exhibited a lower free-energy barrier for fibril growth but also a lower stability compared with the sAD-dominant fibril morphology, resulting in the time-dependent population change consistent with experimental observations. Additionally, we studied the effect of the Bri2 BRICHOS domain, an endogenous protein that has been reported to inhibit Aβ aggregation by preferential binding to fibrils, as one of the possible environmental factors. The Bri2 BRICHOS domain showed stronger binding to the fAD-dominant fibril than the sAD-dominant fibril in silico, suggesting a more effective suppression of fAD-dominant fibril formation. This result explains the high population of the sAD-dominant fibril morphology in sporadic cases with normal Bri2 functions. Genetic predisposition in fAD, on the other hand, might impair or overwhelm Bri2 functions, leading to a high population of fAD-associated fibril morphology. Together, our computational findings provide a theoretical framework for elucidating the AD subtypes entailed by distinct dominant amyloid fibril morphologies.

2024-08-01·Pathology International

Exosomal miR‐196a‐5p contributes to esophageal squamous cell carcinoma malignant progression by inhibiting ITM2B

Article

作者: Zhang, Fan ; Cai, Jun ; Zhu, Yan ; Li, Shuang ; Zeng, Hai ; Huang, Min

AbstractExosomes from cancer cells function as carriers to spread or transport specific microRNAs (miRNAs) to distant sites to exert their effects, but the mechanism of exosomal miRNA action in esophageal squamous cell carcinoma (ESCC) has not been fully explained. Therefore, in this study, we were interested in the impact of exosomal miR‐196a‐5p in ESCC progression. We found that miR‐196a‐5p was expressed enriched in clinical tissues, ESCC cells, and exosomes. Functionally, depletion of miR‐196a‐5p impeded ESCC cell growth, migration, and invasion, whereas overexpression of miR‐196a‐5p produced the opposite results. Moreover, enhancement of exosomal miR‐196a‐5p in recipient ESCC cells triggered more intense proliferation and migration. Mechanistically, we identified integral membrane protein 2B (ITM2B) as a direct target of miR‐196a‐5p. Silencing of ITM2B partially counteracted the inhibitory effect of miR‐196a‐5p inhibitors on the malignant phenotype of ESCC. Furthermore, in vivo, lower miR‐196a‐5p levels triggered by the introduction of antagomiR‐196a‐5p resulted in the generation of smaller volume and weight xenograft tumors. Thus, our results demonstrated novel mechanisms of exosomal and intracellular miR‐196a‐5p‐mediated ESCC growth and migration and identify the interaction of miR‐196a‐5p with ITM2B. These works might provide new targets and basis for the development of clinical treatment options for ESCC.

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