APP mimetic peptide as a potential therapeutic target to reduce amyloid generation

APP 模拟肽作为减少淀粉样蛋白生成的潜在治疗靶点

基本信息

批准号：
10205688
负责人：
ANGELA HO
金额：
$ 45.38万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10205688
关键词：
APBA2 gene Abeta synthesis Adaptor Signaling Protein Affinity Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Attenuated Binding Binding Proteins Biochemical Biochemistry Bioinformatics Biological Blood - brain barrier anatomy Brain Catalytic Domain Cells Cleaved cell Collaborations Complex Cytoplasmic Tail Data Development Disease Drug Design Electrophysiology (science)Endocytosis Endosomes Engineering Event Family Functional disorder Generations Genus Mentha Goals In Vitro Laboratories Lead Mediating Memory impairment Metabolic Molecular Biology Molecular Neurobiology Mouse Protein Mus Mutant Strains Mice Neurobiology Neurons PTB Domain Pathogenicity Pathologic Pathology Pathway interactions Peptides Permeability Proteins Proteolytic Processing Proteomics Research Personnel Resolution Signal Transduction Sorting - Cell Movement Specificity Synapses Testing Therapeutic Three-Dimensional Imaging Toxic effect Work abeta accumulation amyloid precursor protein processing beta secretase design experimental study gamma secretase improved in vivo in vivo Model inhibitor/antagonist insight interdisciplinary approach mouse genetics mouse model neuroinflammation neuron loss neurotoxicity new therapeutic target novel novel therapeutic intervention peptidomimetics presenilin-1 prevent protein protein interaction protein transport side effect tau aggregation therapeutic target

项目摘要

Amyloid-β (Aβ) generation is a key pathological event in Alzheimer's disease (AD). Aβ is produced by the sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ- secretases. APP endocytosis is an important step in Aβ generation. APP is internalized to endosomes where APP is cleaved by β-secretase, initiating the amyloidogenic pathway. The sorting signal that regulates APP endocytic processing required for Aβ generation is the highly conserved endocytic YENPTY sequence located in the cytoplasmic region of APP. APP mice that lack the endocytic YENPTY motif have reduced APP internalization and lower brain Aβ levels. Through our studies, we found Mints (also known as APP binding family A, APBA) are a family of neuronal adaptor proteins that bind directly to the endocytic YENPTY motif of APP and are essential for regulating APP endocytosis and amyloidgenic processing. In addition, Mints interact with presenilin-1 (PS1), the catalytic core of the γ-secretase complex, facilitating APP-PS1 colocalization and promoting Aβ production. Further, we found that loss of any one of the three Mint proteins decreases Aβ production in aging mice and mouse models of AD. Together, we hypothesize that the APP-Mint interaction is a potential and novel therapeutic target to selectively reduce Aβ production in AD. We identified a novel cell-permeable APP mimetic peptide (TAT-APPMP) that interferes with the APP-Mint interaction. The TAT-APPMP is designed to outcompete endogenous APP binding to Mints to reduce Aβ production. Preliminary data reveals that treatment of primary neuronal cultures from an AD mouse model with TAT-APPMP reduced Aβ production with minimal toxicity. This provides compelling evidence that the APP-Mint interface is a viable therapeutic target for AD treatment and is expected to have strong translational implications. However, the biological characterization of the APPMP, examining its specificity, efficacy and its potential for in vivo AD treatment is lacking. The overall goal of this proposal is to determine the specificity of the cell-permeable APPMP to disrupt the APP-Mint interaction and reduce Aβ accumulation in AD mouse models.

β 淀粉样蛋白 (Aβ) 的产生是阿尔茨海默病 (AD) 中的一个关键病理事件。 β- 和 γ- APP 分泌酶对淀粉样前体蛋白 (APP) 进行连续蛋白水解加工。内吞作用是 APP 内化到内体中的重要步骤。被 β-分泌酶裂解，启动淀粉样蛋白生成途径调节 APP 的分选信号。 Aβ 生成所需的内吞加工是高度保守的内吞 YENPTY 序列位于缺乏内吞 YENPTY 基序的 APP 小鼠的细胞质区域的蛋白减少了。 APP 内化和降低大脑 Aβ 水平通过我们的研究，我们发现了 Mints（也称为 APP）。结合家族 A (APBA) 是直接与内吞细胞结合的神经接头蛋白家族 APP 的 YENPTY 基序对于调节 APP 内吞作用和淀粉样蛋白生成过程至关重要。此外，薄荷与 γ-分泌酶复合物的催化核心 presenilin-1 (PS1) 相互作用，促进 APP-PS1 共定位并促进 Aβ 产生，此外，我们发现三者中任何一项的缺失。薄荷蛋白会降低衰老小鼠和 AD 小鼠模型中 Aβ 的产生，我们共同努力。 APP-Mint 相互作用是选择性减少 Aβ 的潜在新型治疗靶点我们发现了一种可干扰 AD 的新型细胞渗透性 APP 模拟肽 (TAT-APPMP)。 TAT-APPMP 旨在竞争内源性 APP 的结合。薄荷糖可减少 Aβ 的产生。初步数据表明，对原代神经元培养物的治疗。使用 TAT-APPMP 的 AD 小鼠模型减少了 Aβ 的产生，且毒性最小。令人信服的证据表明 APP-Mint 接口是 AD 治疗的可行治疗目标，并且预计具有很强的转化意义然而，APPMP 的生物学特征，缺乏检查其特异性、功效及其体内 AD 治疗潜力的总体目标。该提案旨在确定细胞渗透性 APPMP 破坏 APP-Mint 的特异性 AD 小鼠模型中的相互作用并减少 Aβ 积累。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tight control of the APP-Mint1 interaction in regulating amyloid production.

严格控制 APP-Mint1 相互作用来调节淀粉样蛋白的产生。

DOI：
发表时间：
2023-10-15
期刊：
影响因子：
2.9
作者：
Henry, Shawna M;Kistler, Sabrina A;Lagani, Gavin D;Bartling, Christian R O;Özcelik, Dennis;Sereikaite, Vita;Strømgaard, Kristian;Beffert, Uwe;Ho, Angela
通讯作者：
Ho, Angela

Targeting the APP-Mint2 Protein-Protein Interaction with a Peptide-Based Inhibitor Reduces Amyloid-β Formation.

使用基于肽的抑制剂靶向 APP-Mint2 蛋白质-蛋白质相互作用可减少淀粉样蛋白-β 的形成。

DOI：
10.1021/jacs.0c10696
发表时间：
2021-01-20
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Bartling CRO;Jensen TMT;Henry SM;Colliander AL;Sereikaite V;Wenzler M;Jain P;Maric HM;Harpsøe K;Pedersen SW;Clemmensen LS;Haugaard-Kedström LM;Gloriam DE;Ho A;Strømgaard K
通讯作者：
Strømgaard K