Aminopeptidases for Neurotoxic Pyroglutamate Beta-Amyloid of Alzheimers Disease

氨基肽酶治疗阿尔茨海默病的神经毒性焦谷氨酸β-淀粉样蛋白

• 批准号: 8690732
• 负责人: Vivian Y. H Hook
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690732
• 关键词: Address; Alanine; Alzheimer' s Disease; Amino Acids; Aminopeptidase; Amyloid beta-Protein; Aspartate; Behavioral; Brain; Brain region; Cattle; Cell Death; Cells; Chromaffin Cells; Clinical; Collection; Cyclization; Data; Development; Disease; Drug Targeting; Enzymes; Event; Excision; Functional disorder; Future; Gene Expression; Gene Silencing; Glutamates; Goals; Hippocampus (Brain); Human; Human Genome; Immunoprecipitation; Investigation; Isoenzymes; Knock-out; Lead; Mass Spectrum Analysis; Memory; Memory Loss; Memory impairment; Microscopy; Modeling; Modification; Molecular Cloning; Mus; N-terminal; Nerve Degeneration; Neuroblastoma; Neurons; Peptide Hydrolases; Peptides; Production; Property; Pyroglutamate; Rattus; Regulation; Role; Secretory Vesicles; Senile Plaques; Severities; Small Interfering RNA; Therapeutic Agents; Toxic effect; Transgenic Organisms; Ubenimex; United States National Institutes of Health; alanine aminopeptidase; amastatin; amyloid peptide; base; glutaminyl-peptide cyclotransferase; glutamyl aminopeptidase; improved; inhibitor/antagonist; mouse model; neuron loss; neurotoxic; neurotoxicity; new technology; normal aging; novel; peptide A; peptide hormone; public health relevance; small molecule

DESCRIPTION (provided by applicant): The N-terminal truncated pyroglutamate (pGlu) modified forms of beta-amyloid (A ¿), pGluA ¿ (3-40/42) (referred to as pGluA ¿), display high neurotoxicity, neurodegeneration and memory loss in Alzheimer's disease. Notably, pGluA ¿ is abundant in AD brains and is present at levels greater than A¿ (1-40/42). The pGluA ¿ accelerates formation of A¿ and pGluA ¿ oligomers that cause neurotoxic cell death and memory deficits in AD. The pGluA ¿ (3-40/42) peptides begin with N-terminal glutamate, the third amino acid of A¿ (1-40/42). pGluA¿ peptides are generated from A ¿ (1-40/42) by aminopeptidases that remove the N-terminal aspartate and alanine residues, followed by cyclization of the N-terminal glutamate. The aminopeptidases required to generate pGluA¿ peptides have not yet been elucidated. Therefore, the goal of this project will be to identify the aminopeptidase mechanisms responsible for generating neurotoxic pGluA¿ that participates with A ¿ in development of AD. Results can provide novel protease targets for Alzheimer's disease. The hypothesis of this project is that the aspartate aminopeptidase and alanine aminopeptidase enzymes generate A ¿ (3-40/42) which is converted to pGluA¿(3-40/42) by glutaminyl cyclase (QC). This hypothesis is supported by our preliminary data demonstrating the presence of aspartate and alanine aminopeptidase activities in secretory vesicles that contain pGluA¿ (3-40/42) and A¿ (1-40/42). This hypothesis will be assessed in three specific aims to (1) identify aspartate and alanine aminopeptidases in A ¿ -producing secretory vesicles that remove the N-terminal Asp and Ala residues from A ¿ (1-40/42), (2) evaluate identified aminopeptidases by gene silencing and expression for their roles in producing pGluA¿ (3-40/42), and (3) evaluate inhibitors of these aminopeptidase activities to reduce production of pGluA¿ (3- 40/42). This project will identify new aminopeptidase mechanisms for producing neurotoxic pGluA¿ peptides. Results will also yield candidate inhibitors of these aminopeptidases for future investigation of aminopeptidase regulation in Alzheimer's disease.

描述（由申请人提供）：β-淀粉样蛋白（A ¿）的 N 端截短的焦谷氨酸（pGlu）修饰形式，pGluA ¿ (3-40/42)（称为 pGluA ¿），在阿尔茨海默病中表现出高神经毒性、神经变性和记忆丧失。 AD 大脑中含量丰富，且含量高于 A¿ (1-40/42)。加速A¿的形成和 pGluA ¿导致 AD 中神经毒性细胞死亡和记忆缺陷的寡聚体 ¿ (3-40/42) 肽以 N 端谷氨酸（A¿ 的第三个氨基酸）开头(1-40/42)。肽由 A ¿ 生成(1-40/42) 通过氨肽酶去除 N 端天冬氨酸和丙氨酸残基，然后环化 N 端谷氨酸 生成 pGluA 所需的氨肽酶。因此，该项目的目标是确定负责产生神经毒性 pGluA 的氨肽酶机制。与 A ¿ 一起参与结果可以为阿尔茨海默氏病提供新的蛋白酶靶标。该项目的假设是天冬氨酸氨肽酶和丙氨酸氨肽酶产生A ¿ (3-40/42) 转换为 pGluA¿ (3-40/42) 通过谷氨酰胺酰环化酶 (QC)，我们的初步数据证明了含有 pGluA 的分泌囊泡中存在天冬氨酸和丙氨酸氨基肽酶活性。 (3-40/42) 和 A¿ (1-40/42)。该假设将在三个具体目标中进行评估，以 (1) 识别 A ¿ 中的天冬氨酸和丙氨酸氨肽酶。 -产生分泌囊泡，去除A中的N端天冬氨酸和丙氨酸残基 ¿ (1-40/42), (2) 通过基因沉默和表达评估已鉴定的氨肽酶在产生 pGluA 中的作用¿ (3-40/42) 和 (3) 评估这些氨肽酶活性的抑制剂以减少 pGluA 的产生(3- 40/42)。该项目将确定产生神经毒性 pGluA 的新氨肽酶机制。结果还将产生这些氨肽酶的候选抑制剂，用于未来研究阿尔茨海默氏病的氨肽酶调节。

项目成果

Pyroglutamate-amyloid-β and glutaminyl cyclase are colocalized with amyloid-β in secretory vesicles and undergo activity-dependent, regulated secretion.

焦谷氨酸-淀粉样蛋白-β 和谷氨酰胺酰环化酶与淀粉样蛋白-β 共定位于分泌囊泡中，并进行活性依赖性、受调节的分泌。

• 发表时间: 2014
• 作者: Cynis, Holger;Funkelstein, Lydiane;Toneff, Thomas;Mosier, Charles;Ziegler, Michael;Koch, Birgit;Demuth, Hans;Hook, Vivian
• 通讯作者: Hook, Vivian