Development of Myeloperoxidase Inhibitors to Treat Alzheimer's Disease

描述（由申请人提供）：本研究的总体目标是开发口服髓过氧化物酶MPO抑制剂，用于治疗阿尔茨海默病。MPO是白细胞中丰富的酶，但其表达可在阿尔茨海默病的星形胶质细胞中诱导。MPO的这种异常表达可导致脂质和蛋白质的氧化，导致组织损伤和细胞死亡，从而导致记忆丧失。一种有效而安全的MPO抑制剂可能有助于治疗阿尔茨海默病。我们开发了一种新的小鼠模型来评估MPO在阿尔茨海默病中的作用。在具体目标1中，我们建议提高在寻找MPO抑制剂的筛选中鉴定的命中的效力。在具体目标2中，我们建议在阿尔茨海默病小鼠模型中测试几种MPO抑制剂。将使用生化和行为/认知测试对小鼠进行评价。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to develop orally active inhibitors of myeloperoxidase MPO as a treatment forAlzheimer's disease. MPO is an abundant enzyme in leukocytes but its expression can be induced in astrocytes in Alzheimer's disease. This abnormal expression of MPO can lead to the oxidation of lipids and proteins leading to tissue damage and cell death resulting in loss of memory. A potent and safe inhibitor of MPO could be helpful in the treatment of Alzheimer's disease. We have developed novel mouse model to evaluate the role of MPO in Alzheimer's disease. In Specific Aim 1 We propose to improve the potency of hits identified in a screen looking for inhibitors of MPO. In Specific Aim 2 we propose to test several of the MPO inhibitors in a mouse model of Alzheimer's disease. The mice will be evaluated using both biochemical and behavioral/cognitive tests.