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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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）的关键病理事件。Aβ是由 淀粉样前体蛋白（APP）通过β-和γ-分泌酶的连续蛋白水解加工。APP 内吞作用是Aβ生成的重要步骤。APP被内化到内体，APP在内体中 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 缺乏内吞YENPTY基序的APP小鼠具有减少的 APP内化和降低脑Aβ水平。通过我们的研究，我们发现薄荷糖（也称为APP 结合家族A，APBA）是直接结合内吞蛋白的神经元衔接蛋白家族。 APP的YENPTY基序，并且对于调节APP内吞作用和淀粉样蛋白形成加工是必需的。在 此外，薄荷与早老素-1（PS1）相互作用，后者是γ-分泌酶复合物的催化核心， APP-PS1共定位和促进Aβ产生。此外，我们发现，失去这三个中的任何一个， 薄荷蛋白减少衰老小鼠和AD小鼠模型中的Aβ产生。我们一起假设 APP-Mint相互作用是选择性降低Aβ的潜在和新的治疗靶点 生产AD。我们鉴定了一种新的细胞渗透性APP模拟肽（TAT-APPMP）， 与APP-Mint互动。TAT-APPMP被设计为胜过内源性APP结合， 薄荷糖减少Aβ生成。初步数据显示，对来自 用TAT-APPMP的AD小鼠模型以最小的毒性减少Aβ产生。这提供 令人信服的证据表明，APP-Mint界面是AD治疗的可行治疗靶点， 预计会产生强烈的翻译影响。然而，APPMP的生物学特性， 缺乏对其特异性、功效及其在体内AD治疗中的潜力的检验。的总目标 该建议是确定可渗透细胞的APPMP破坏APP-Mint的特异性 在AD小鼠模型中的相互作用和减少Aβ积累。

项目成果

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

• 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

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: 10.1016/j.brainres.2023.148496
• 发表时间: 2023
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Henry,ShawnaM;Kistler,SabrinaA;Lagani,GavinD;Bartling,ChristianRO;Özcelik,Dennis;Sereikaite,Vita;Strømgaard,Kristian;Beffert,Uwe;Ho,Angela
• 通讯作者: Ho,Angela