Interleukin-1 and Memory Loss in Aging

描述(由申请人提供)： 这项赠款的主要假设是慢性炎症和细胞凋亡导致海马区依赖的行为缺陷。越来越多的证据表明，IL1b在学习和记忆中起着重要作用。在老年大鼠中，IL1b增加，这与海马区突触可塑性和认知任务表现的下降有关。关于这种细胞因子在学习和记忆过程中的作用，有几个问题仍然没有答案。1)IL-1水平升高是否直接导致正常年龄的学习和记忆障碍？2)幼年大鼠生理水平的IL-1存在是否是记忆获得和存储的限制步骤？3)最后，IL-1影响记忆的机制是什么？许多老年人表现出学习和记忆过程的缺陷，以及大脑不同区域神经元数量的减少。然而，更准确地计算神经元的程序的发展，例如使用体视学，已经引起了人们对神经元数量下降的怀疑，这是通过正常衰老过程中的神经元死亡来实现的。如果缺乏显著的神经元丢失，可以在老年人的大脑中检测到神经退化的几个病理特征，例如典型的帕金森氏病的路易小体的存在，以及阿尔茨海默病的典型的老年斑。因此，从这些观察中提出的问题是，除了参与神经元死亡外，细胞凋亡是否会影响正常衰老过程中认知过程的下降。半胱氨酸天冬氨酸氨基转移酶是一个蛋白水解酶家族，在长期空间记忆存储中起着关键作用。半胱氨酸天冬氨酸氨基转移酶-1(IL-1b转换酶)通过IL-1b的中间产物参与细胞凋亡和炎症的激活。已有研究表明，抑制caspase-1可通过减少细胞凋亡和炎性细胞因子的产生而发挥脑缺血的神经保护作用。尽管IL-1b在神经退行性疾病中高表达，参与认知障碍，并诱导神经胶质细胞培养的细胞死亡，但IL-1b和caspase是否相互作用表达其对学习和记忆的影响仍不清楚。

DESCRIPTION (provided by applicant): The primary hypothesis of this grant is that chronic inflammation and apoptosis lead to hippocampusdependent behavioral deficits. There is accumulating evidence for the role of IL1b in learning and memory. In aged rats there is an increase in IL1b that has been implicated in declines of synaptic plasticity in the hippocampus and performance on cognitive tasks. There are several questions about the role of this cytokine in learning and memory processes that remain unanswered. 1) Are increased levels of IL-1 directly responsible for deficits in learning and memory occurring in normal age? 2) Is IL-1 presence at physiological levels in young rats a limiting-step in the acquisition and storage of memory? 3) and finally, which are the mechanisms by which IL-1 affects memory? Many elderly individuals exhibit deficits in learning and memory processes, as well as decreased numbers of neurons in different regions of the brain. However, the development of more accurate procedures for counting neurons, such as the use of stereology, has raised doubts about the decline in neurons number, via neuronal death during normal aging. If significant neuronal loss is lacking, several pathological features of neurodegeneration, such as the presence of Lewy bodies, typical of Parkinson's disease, and senile plaques, typical of Alzheimer's disease, can be detected in brains of aged individuals. So, the question that has been raised from these observations is whether or not apoptosis, beyond its involvement in neuronal death, affects the decline in cognitive processes occurring during normal aging. Caspases are a family of proteases that play a critical role in long-term spatial memory storage. Caspase-1 (IL-1b converting enzyme) has the peculiarity of being involved in the activation of both apoptosis and inflammation, through the intermediate of IL-1b. It has been shown that inhibition of caspase-1 induces neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proirrflammatory cytokines. Although interleukin-1b is highly expressed in neurodegenerative disease, is involved in cognitive impairment, and induces cell death in glial cells cultures, whether IL-1b and caspase interact each other to express their effects on learning and memory, it is still unknown.