PTEN, Cell Cycle and Neurofibrillary Degeneration

摘要 在阿尔茨海默病（AD）中，神经元缠结（NFT）和大量神经元死亡/损失的出现是阿尔茨海默病（AD）的特征。 被广泛接受为两个主要标志。虽然NFT与 在几种神经退行性疾病中的细胞死亡，称为tau蛋白病，最值得注意的是在AD中， 导致这种神经元细胞慢性丧失的分子机制仍然不清楚。异位表达 细胞周期标志物，表明异常的细胞周期折返，已被报道与 转基因（Tg）小鼠和人AD脑中的神经元死亡。因此，细胞周期假说是 提出，这些细胞周期事件（CCE）发挥了核心的致病作用，并代表了第一步， 这种毁灭性疾病的发展。这个模型补充了淀粉样蛋白假说。然而，直接 缺乏CCE的致病作用的证据，并且上游调节因子未知。我们现在确认 肿瘤抑制因子PTEN作为一个上游因子，控制有丝分裂后神经元中的CCE， 发现核PTEN调节神经元细胞周期。此外，这种细胞周期调节功能是 在空间上与PTEN在PI 3激酶-Akt信号通路中的经典作用分离， 主要是通过细胞质蛋白。在AD相关性中发现了PTEN（特别是核PTEN）的缺失。 Tg小鼠和人类患病大脑中与CCE相关的区域。我们推测， 核内PTEN基因是CCEs的早期致病因子之一， 转移不仅可以阻断CCE，而且可以阻止随后的神经变性。本文提出的研究将 目的验证细胞周期假说，并在AD小鼠模型中检测细胞核中的PTEN。四个具体目标 1）定量分析轻度认知障碍患者的PTEN/pAkt谱和CCE， 2）分析三重Tg小鼠模型中的pAkt水平及其激酶活性， AD 3）研究三重Tg模型中CCE的早期可能原因，以及4）评估 慢病毒递送的核PTEN治疗三重Tg中的CCE和神经变性的有效性 小鼠模型这项工作将有助于未来设计新的治疗干预措施，不仅 旨在缓解疾病，但也旨在改善疾病机制。除了治疗，这项研究也可能有助于 验证CCE作为疾病诊断的早期标志物 我们的目的是验证两个新的概念，即细胞周期异常事件是重要的疾病之一， 研究表明，慢病毒介导的核PTEN基因转移可以预防这些事件， 在AD小鼠模型中。这项工作将对开发一类新的细胞周期抑制剂产生重大影响。 一旦这些概念得到验证，AD的未来预防和治疗策略。

Abstract In Alzheimer's disease (AD), the appearance of neurofibrillary tangles (NFTs) and massive neuronal death/loss in selected brain regions are widely accepted as the two major hallmarks. Although NFTs are coincident with cell death in several neurodegenerative diseases, known as tauopathies, and most notably in AD, the molecular mechanisms leading to this chronic loss of neuronal cells is still not understood. Ectopic expression of cell cycle markers, indicating aberrant cell cycle reentry, has been reported to be associated with neuronal death in both transgenic (Tg) mouse and human AD brains. Hence, a ¿cell cycle hypothesis¿ was proposed that these cell cycle events (CCEs) play a central causative role and represent the first step in the development of this devastating disease. This model complements the ¿amyloid hypothesis.¿. However, direct proof of a causative role for CCEs is lacking and the upstream regulatory factors are unknown. We now identify the tumor suppressor PTEN as an upstream factor governing the CCEs in post-mitotic neurons based on our finding that nuclear PTEN regulates the neuronal cell cycle. Moreover, this cell cycle regulatory function is spatially separated from the classic role of PTEN in the PI3 kinase-Akt signaling pathway, which is mediated primarily by the cytoplasmic protein. Loss of PTEN (nuclear PTEN, in particular) was found in AD-relevant regions in both Tg mice and human diseased brains which correlated with CCEs. We speculate that this loss of nuclear PTEN is one of the early causative factors in CCEs and that lentivirus-delivered nuclear PTEN gene transfer may not only block CCEs but also halt subsequent neurodegeneration. Studies proposed herein will aim to validate the cell cycle hypothesis and examine nuclear PTEN in an AD mouse model. Four specific aims are proposed to achieve this goal: 1) Quantitative analysis of PTEN/pAkt profiles and CCEs in mild cognitive impairment (MCI) and AD brains 2) Profile the pAkt level and its kinase activity in the triple Tg mouse model of AD 3) To investigate an early possible cause for CCEs in the triple Tg model and 4) To assess the effectiveness of lentivirus-delivered nuclear PTEN in treating CCEs and neurodegeneration in the triple Tg mouse model. This work will be instrumental to the future design of new therapeutic interventions, not only aiming at symptom-relief but also at disease-modifying mechanisms. Besides therapy, this study may also help validate CCEs as an early marker for disease diagnosis Project Narrative We aim to validate two new concepts that aberrant cell cycle events are one of the important disease mechanisms in AD and that lentivirus-delivered nuclear PTEN gene transfer in CNS can prevent these events in an AD mouse model. This work should have great impact on exploring a new class of cell cycle inhibitors in future preventive and treatment strategies of AD once these concepts are validated.