PTEN, Cell Cycle and Neurofibrillary Degeneration

描述（由申请人提供）：在阿尔茨海默病（AD）中，神经原纤维缠结（nft）的出现和特定脑区大量神经元死亡/丢失被广泛认为是两个主要标志。尽管nft在一些神经退行性疾病（称为tau病）中与细胞死亡同时发生，尤其是在AD中，但导致这种神经细胞慢性损失的分子机制仍不清楚。细胞周期标记物的异位表达，表明异常的细胞周期再进入，已被报道与转基因（Tg）小鼠和人AD大脑中的神经元死亡有关。因此，提出了一个“细胞周期假说”，认为这些细胞周期事件（CCEs）起着核心的致病作用，代表了这种毁灭性疾病发展的第一步。这个模型补充了“淀粉样蛋白假说”。然而，缺乏CCEs致病作用的直接证据，上游调控因素尚不清楚。基于我们发现核PTEN调节神经元细胞周期，我们现在确定肿瘤抑制因子PTEN是控制有丝分裂后神经元CCEs的上游因子。此外，这种细胞周期调节功能与PTEN在PI3激酶- akt信号通路中的经典作用在空间上是分离的，PTEN主要由细胞质蛋白介导。在Tg小鼠和人类病变大脑的ad相关区域发现PTEN（特别是核PTEN）的缺失，这与CCEs相关。我们推测核PTEN的缺失是CCEs的早期致病因素之一，慢病毒传递的核PTEN基因转移不仅可以阻断CCEs，还可以阻止随后的神经退行性变。本文提出的研究旨在验证细胞周期假说，并在AD小鼠模型中检测核PTEN。实现这一目标提出了四项具体目标:1)定量分析PTEN / pAkt概要文件和cc在轻度认知障碍(MCI)和广告的大脑2)剖面pAkt三重Tg水平及其激酶活动广告3)小鼠模型,调查早期可能原因的cc三重Tg模型和4)评估的有效性lentivirus-delivered核PTEN在治疗cc和神经退行性变的三重Tg小鼠模型。这项工作将有助于未来设计新的治疗干预措施，不仅针对症状缓解，而且针对疾病调节机制。除了治疗之外，这项研究也可能有助于验证CCEs作为疾病诊断的早期标志。公共卫生相关性：我们旨在验证两个新概念，即异常细胞周期事件是阿尔茨海默病的重要疾病机制之一，以及慢病毒在中枢神经系统中传递核PTEN基因可以在阿尔茨海默病小鼠模型中预防这些事件。一旦这些概念得到验证，这项工作将对探索一类新的细胞周期抑制剂在未来AD的预防和治疗策略中产生重大影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.