Notch Signaling in the Adult, Aging and Diseased Brain

脑老化和神经退行性疾病的主要问题之一是由神经突和突触连接的不稳定引起的认知障碍，随后是神经元的变性和损失。因此，阐明调节神经突和突触生长和稳定的分子机制不仅可以帮助我们更好地理解这些事件，而且还可以为开发新的预防和治疗方法提供信息。最近在包括我们在内的几个实验室中获得的证据表明，通过Notch受体的接触依赖性信号传导在大脑皮层中神经突和突触连接的生长和稳定中起作用，Notch受体传统上仅与胚胎发育有关。我们还证明，内源性Notch活性在发育和成熟的皮质神经元可以调制外源性应用的Notch配体三角洲和锯齿状，和细胞内的蛋白Numb，Numb样，和Deltex。此外，已在早老素（PS）基因中鉴定出引起早发性阿尔茨海默病（AD）的许多突变，这些突变已被证明不仅对于γ-分泌酶介导的淀粉样前体蛋白（APP）加工是必需的，而且对于Notch受体的运输、内切蛋白水解加工和活性也是必需的。我们的工作假设是，在衰老和许多神经退行性疾病中，神经元连接的降解与Notch信号通路基因的表达和活性的变化相关，这可能直接或间接地导致潜在的发病机制。如果是这样的话，那么找到一种控制Notch信号的方法，无论是上游，通过配体，还是下游，通过细胞内蛋白质，都可以提供一种减缓或改变大脑皮层衰老和记忆障碍结果的方法。我们提出了三个逻辑相关的具体目标：（I）表达和亚细胞定位的Notch信号分子在正常和异常的成人大脑皮层;（II）操纵的稳定性和可修改的皮质神经突和突触的Notch活性的影响;（III）早老蛋白的表达，蛋白水解过程中的作用，和活性的Notch受体在皮质神经元。我们有很好的初步数据，我们的期望是，这种范围和方法多样性的研究将提供深入了解神经变性的发病机制，并可能产生缓解或减缓其进展的方法。

One of the major problems with brain aging and neurodegenerative diseases is the cognitive impairment caused by the destabilization of neurites and synaptic connections followed by the degeneration and loss of neurons. Thus, elucidating the molecular mechanisms that regulate the growth and stabilization of neurites and synapses may not only help us better understand these events, but may also provide information for developing new preventive and therapeutic approaches. Recent evidence obtained in several laboratories, including ours, has implicated contact- dependent signaling via the Notch receptors, which has been traditionally associated only with embryonic development, in the growth and stabilization of neurites and synaptic connections in the cerebral cortex. We have also demonstrated that endogenous Notch activity in both developing and mature cortical neurons can be modulated by exogenously applying the Notch ligands Delta and Jagged, and the intracellular proteins Numb, Numb-like, and Deltex. In addition, numerous mutations causing early-onset Alzheimer's Disease (AD) have been identified in the presenilin (PS) genes, which have been shown to be necessary not only for gamma-secretase-mediated processing of amyloid precursor protein (APP), but also for the trafficking, endoproteolytic processing, and activity of the Notch receptors. Our working hypothesis is that in aging and many neurodegenerative disorders, the degradation of neuronal connections is associated with changes in the expression and activity of the Notch signaling pathway genes, which may directly-or indirectly contribute to the underlying pathogenesis. If so, then finding a way to control Notch signaling, either upstream, via ligands, or downstream, via intracellular proteins, could provide a means to slow down or change the outcome of aging and memory disorders in the cerebral cortex. We propose three logistically related Specific Aims: (I) The expression and subcellular localization of Notch signaling molecules in the normal and abnormal adult cerebral cortex; (II) The effect of manipulating Notch activity on the stability and modifiability of cortical neurites and synapses; and (III) The role of preseniiins in the expression, endoproteolytic processing, and activity of Notch receptors in the cortical neurons. We have promising preliminary data and our expectation is that research of this scope and methodological diversity will provide insight into the pathogenesis of neurodegeneration and possibly generate the means to alleviate or slow its progression.