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

描述（申请人提供）：随着阿尔茨海默病（AD）人口的快速增长，目前没有治愈的治疗方法。此次重新提交的STTR提案的目标是开展一项关于普兰林肽的临床前研究，以证明其治疗AD的潜在方法。根据审稿人的意见，我们对提案进行了较大幅度的修改。普兰林肽是FDA批准的治疗糖尿病的药物，是一种胰淀素类似物。由于糖尿病增加了AD的风险，像普兰林肽这样的糖尿病药物可能对AD有益。此外，我们的初步研究还表明，胰淀素类似物可能会清除AD大脑中的神经毒性淀粉样蛋白-β肽（Aβ）。因此，研究胰淀素及其类似物是否可以作为治疗AD的药物是势在必行的。本STTR提案的目的是评估普兰林肽对AD小鼠模型淀粉样前体蛋白转基因（APP）小鼠的影响。本研究的中心假设是，普兰林肽注射会引起血液中Aβ的增加，普兰林肽治疗会减少Aβ从大脑进入血液，从而改善APP转基因小鼠的认知功能障碍。APP小鼠每天服用一剂普兰林肽，并评估其运动、协调和学习能力的改善情况。我们将评估和比较药物治疗与安慰剂治疗的大脑皮层和海马体中可溶性和沉淀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.