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

描述(申请人提供)：由于阿尔茨海默病(AD)人口迅速增长，目前还没有治愈的方法。重新提交的STTR提案的目的是用普拉林肽进行一项临床前研究，以证明AD的潜在治疗方法。我们已根据评审员的意见，对建议作出重大修订。普拉林肽是FDA批准的治疗糖尿病的药物，是胰淀素类似物。由于糖尿病增加了AD的风险，作为一种非标签药物，像普拉林肽这样的糖尿病药物可能对AD有利。此外，我们的初步研究还表明，淀粉素类似物可以将神经毒性淀粉样蛋白β肽(Aβ)从AD大脑中移除。因此，研究胰淀素及其类似物能否作为治疗阿尔茨海默病的药物势在必行。这项建议的目的是评估普拉林肽对淀粉样前体蛋白转基因(APP)小鼠的影响，这是一种AD小鼠模型。本研究的中心假说是，普林肽注射会引起血液中Aβ的增加，普林肽治疗会减少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小鼠将每天服用一剂普拉林肽，并将进行评估，以评估改善的运动、协调和学习能力。我们将评估和比较接受药物和安慰剂治疗的大脑皮质和海马区中可溶性和沉淀性Aβ的水平。我们还将检查葡萄糖代谢生物标志物和大脑中tau/p-tau的水平。

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.