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.

淀粉样蛋白-β (a β)的生成是阿尔茨海默病（AD）的关键病理事件。Aβ是由

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