Removal of Amyloid-beta Peptides from the Alzheimer's Brain

描述（由申请人提供）：由于阿尔茨海默病（AD）人口迅速增长，目前没有治愈治疗方法。此次重新提交的STTR提案的目的是对普兰林肽进行临床前研究，以证明其治疗AD的潜力。我们根据审查人员的意见对提案作了重大修改。普兰林肽是FDA批准的用于糖尿病的药物，并且是胰淀素类似物。由于糖尿病增加了AD的风险，因此糖尿病药物如普兰林肽作为标签外药物可能对AD有益。此外，我们的初步研究还表明，胰淀素类似物可以将神经毒性淀粉样β肽（Aβ）从AD脑中清除。因此，迫切需要研究胰淀素及其类似物是否可以用作治疗AD的药物。本STTR提案的目的是评估普兰林肽对淀粉样前体蛋白转基因（APP）小鼠（AD小鼠模型）的影响。本研究的中心假设是注射普兰林肽将引起血液中Aβ的增加，普兰林肽治疗将减少Aβ从大脑进入血液，以改善APP转基因小鼠的认知障碍。APP小鼠将每天用一个剂量的普兰林肽处理，并将进行评估改善的运动、协调和学习能力。我们将评估和比较药物与安慰剂治疗组大脑皮质和海马中可溶性和沉淀性Aβ的水平。我们还将检查大脑中的葡萄糖代谢生物标志物和tau/p-tau水平。

DESCRIPTION (provided by applicant): As the Alzheimer's disease (AD) population is growing rapidly, currently there are no cure treatments. The goal of this resubmitted STTR proposal is to conduct a preclinical study with pramlintide to prove a potential treatment for AD. We have revised the proposal significantly according to the reviewers' comments. Pramlintide is an FDA approved drug for diabetes and is an amylin analog. As diabetes increases the risk of AD, diabetic medications like pramlintide may be beneficial for AD as an off-label drug. Additionally, our preliminary study also suggests that amylin analogs may remove the neurotoxic amyloid-β peptide (Aβ) out of the AD brain. It is therefore imperative to study whether amylin and its analogs can be used as a drug for the treatment of AD. The goal of this STTR proposal is to evaluate the effect of pramlintide on the amyloid precursor protein transgenic (APP) mice, an AD mouse model. The central hypothesis of this study is that the pramlintide injection will provoke an increase of Aβ in the blood, and the pramlintide treatment will reduce Aβ from the brain into blood to improve cognitive impairment in the APP transgenic mice. The APP mice will be treated with one dose of pramlintide on a daily basis, and will be conducted to assess improved movement, coordination and learning capabilities. We will evaluate and compare the levels of soluble and precipitated Aβ in the cortex and hippocampus in the brains treated by the drug vs. placebo. We will also examine glucose metabolic biomarkers and tau/p-tau levels in the brains.