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）人群的迅速增长，目前尚无治愈方法。此次重新提交的 STTR 提案的目的是利用普兰林肽进行临床前研究，以证明其是 AD 的潜在治疗方法。我们根据审稿人的意见对提案进行了重大修改。普兰林肽是 FDA 批准的糖尿病药物，是胰淀素类似物。由于糖尿病会增加患 AD 的风险，因此普兰林肽等糖尿病药物作为适应证外药物可能对 AD 有益。此外，我们的初步研究还表明，胰淀素类似物可能会去除 AD 大脑中的神经毒性β淀粉样肽 (Aβ)。因此，研究amylin及其类似物是否可以作为治疗AD的药物势在必行。该 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（一种 AD 小鼠模型）的影响。这项研究的中心假设是，普兰林肽注射液会引起血液中Aβ的增加，而普兰林肽治疗会减少大脑中进入血液的Aβ，从而改善APP转基因小鼠的认知障碍。 APP 小鼠将每天接受一剂普兰林肽治疗，并评估运动、协调和学习能力的改善情况。我们将评估和比较药物与安慰剂治疗大脑皮层和海马中可溶性和沉淀 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.