EXOGENOUS INDUCTION OF ALZHEIMER A?-PATHOLOGY IN TRANSGENIC MICE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们已经研究了AD患者和松鼠猴（Saimiri sciureus）中A？的定量和定性特征，松鼠猴是一种密切相关但抗AD的灵长类动物。 通过ELISA，我们发现老年松鼠猴大脑皮层A？水平可以等于或超过AD大脑的水平。 使用免疫沉淀和MALDI-TOF质谱，我们还表明，可溶性和不溶性A肽群体在松鼠猴和AD患者中高度相似。 为了检验这一假设，即在这两个物种中的A <$-多聚体可能呈现致病性不同的形式，我们然后检查了从松鼠猴和AD患者中提取的富含A <$的皮质提取物诱导或播种APP/PS1转基因小鼠中A <$沉积的能力。 将稀释的皮质提取物单侧注射到APP/PS1小鼠的海马中，然后在该区域内源性沉积A？。 对侧半球中的假PBS注射用作内部对照。 在4个月的孵育期后，用A肽的抗体对小鼠大脑进行免疫染色。 在所有实验动物的浸提液注射半球中，沉积增强。 用双重免疫荧光和共聚焦显微镜，我们确定了AD和松鼠猴提取物特有的种子A？沉积的细胞和实质模式。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have examined the quantitative and qualitative characteristics of A¿ in humans with AD and in squirrel monkeys (Saimiri sciureus), a closely related, but AD-resistant, primate species. By ELISA, we found that cortical A¿ levels in aged squirrel monkeys can equal or exceed the levels in AD brain. Using immunoprecipitation and MALDI-TOF mass spectrometry, we have also shown that soluble and insoluble A¿ peptide populations are highly similar in squirrel monkeys and humans with AD. To test the hypothesis that A¿-multimers in the two species may assume pathogenically dissimilar forms, we then examined the ability of A¿-rich cortical extracts from squirrel monkeys and AD patients to induce, or seed, A¿ deposition in APP/PS1 transgenic mice. Dilute cortical extracts were injected unilaterally into the hippocampus of APP/PS1 mice, prior to the endogenous deposition of A¿ in that region. Sham PBS injections in the contralateral hemisphere served as internal controls. After a 4 month incubation period, the mouse brains were immunostained with antibodies to the A¿ peptide. A¿ deposition was enhanced in the extract-injected hemisphere of all experimental animals. With double immunofluorescence and confocal microscopy, we identified cellular and parenchymal patterns of seeded A¿ deposition unique to AD and squirrel monkey extracts.