Use of bone marrow stem cells to treat Alz. Dis

描述(申请人提供)：最近发现抗淀粉样β蛋白(A？)结合并隔离外周A？？的抗体或试剂会产生一种“下沉效应”，即大脑A？？水平明显降低。这种外周清除提供了机会来开发新的策略来减少脑A？作为阿尔茨海默病(AD)的治疗方法。我们建议开发一种新的治疗AD的方法，在这种方法中，骨髓干细胞被慢病毒载体感染，该载体直接表达肽酶neprilysin。然后，受感染的骨髓细胞被移植到接受者身上，接受者将在红细胞表面表达Neprilysin。由于奈普利菌素能有效降解A？，因此血清A？水平会降低，然后大脑A的含量会降低？水平通过“下沉效应”。为了验证这一策略，提出了以下具体目标：(1)在红细胞上表达Neprilysin，并确定其对血浆和脑A？转基因幼年淀粉样前体蛋白(APP TG)小鼠体内淀粉样蛋白水平和淀粉样斑块的形成。慢病毒载体将被用于将neprilysin从供体小鼠的骨髓前体细胞中导入，并将这些被感染的细胞移植到受体APP TG小鼠中。大脑和血浆A？将在长达18个月的时间里监测血浆中的脑纤溶酶活性和大脑中淀粉样斑块的形成。(2)检测老年APP-TG小鼠红细胞表达neprilysin是否能逆转淀粉样斑块的数量。这个目标基本上与第一个相同，除了受体小鼠将是18-20个月大的，我们将确定是否清除血浆A？会导致大脑中预先形成的淀粉样沉积的溶解。 综上所述，这些研究代表了干细胞的一种新用途，它提供了一种清除外周A？的机制，这应该会通过所描述的“下沉效应”导致脑A？？的清除。这代表了一种预防和治疗阿尔茨海默病的新的和潜在的有用的治疗方法。

DESCRIPTION (provided by applicant): It has recently been shown that anti-amyloid beta peptide (A?) antibodies or agents that bind to and sequester A??in the periphery produce a "sink effect" in which brain A? levels are appreciably diminished. This peripheral clearance provides the opportunity to develop new strategies for reducing brain A? as a therapeutic treatment in Alzheimer's disease (AD). We propose to develop a novel method for treating AD in which bone marrow stem cells are infected with a lentiviral vector directing expression of the peptidase neprilysin. The infected bone marrow cells are then transplanted to a recipient whereby the recipient will express neprilysin on the surface of red blood cells. Since neprilysin efficiently degrades A?, the serum A? levels will decrease, followed by a decrease in brain A? levels through the "sink effect". To test this strategy the following specific aims are proposed: (1) to express neprilysin on red blood cells and determine its effect on plasma and brain A? levels and amyloid plaque formation in young amyloid precursor protein transgenic (APP Tg) mice. A lentivirus vector will be used to introduce neprilysin into bone marrow progenitor cells from a donor mouse and transplant these infected cells into a recipient APP Tg mice. Brain and plasma A? levels, neprilysin activity in the plasma, and amyloid plaque formation in the brain will be monitored for up to 18 months. (2) To determine if expression of neprilysin on red blood cells can reverse the number of amyloid plaques in older APP Tg mice. This aim will be essentially the same as the first except that the recipient mice will be 18-20 months old, and we will determine if clearance of plasma A? can lead to dissolution of preformed amyloid deposits in the brain. Taken together these studies represent a novel use of stem cells to provide a mechanism for the clearance of peripheral A?, which should lead to clearance of brain A??through a described "sink effect". This represents a novel and potential useful therapeutic approach for preventing and treating Alzheimer's disease.