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神经突起和突触连接的不稳定导致的认知障碍，继而是神经元的退化和丧失。因此，阐明调控神经突起和突触生长和稳定的分子机制不仅有助于我们更好地了解这些事件，而且可能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获得的证据表明，通过Notch受体的接触依赖信号参与了大脑皮层神经突起和突触连接的生长和稳定，而Notch受体传统上只与胚胎发育有关。我们还证明，发育中和成熟的皮质神经元中的内源性Notch活性都可以通过外源应用Notch配体Delta和Jagge以及细胞内蛋白质Numb、Numb-like和Deltex来调节。此外，在早老素(PS)基因中发现了许多导致早发性阿尔茨海默病(AD)的突变，这不仅是伽马分泌酶介导的淀粉样前体蛋白(APP)处理所必需的，而且对于Notch受体的运输、内蛋白分解处理和活性也是必需的。我们的工作假设是，在衰老和许多神经退行性疾病中，神经元连接的退化与Notch信号通路基因的表达和活性的变化有关，这可能直接或间接地参与了潜在的发病机制。如果是这样的话，那么找到一种方法来控制Notch信号，无论是上游通过配体，还是下游，通过细胞内蛋白，可以提供一种手段来减缓或改变大脑皮层衰老和记忆障碍的结果。我们提出了三个逻辑上相关的特定目标：(I)Notch信号分子在正常和异常成人大脑皮层的表达和亚细胞定位；(Ii)操纵Notch活性对皮质突起和突触稳定性和可调性的影响；(Iii)前肾素在皮质神经元Notch受体表达、内蛋白降解加工和活性中的作用。我们有很有希望的初步数据，我们期望对这种范围和方法多样性的研究将为神经变性的发病机制提供洞察力，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.