Interleukin-1 and Memory Loss in Aging

描述（由申请人提供）： 这项研究的主要假设是慢性炎症和细胞凋亡导致了依赖于海马的行为缺陷。有越来越多的证据表明IL 1b在学习和记忆中的作用。在老年大鼠中，IL 1b的增加与海马中突触可塑性的下降和认知任务的表现有关。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出现学习和记忆缺陷？2)幼鼠生理水平的IL-1存在是记忆获得和储存的限制步骤吗？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，更精确的神经元计数方法的发展，如体视学的使用，引起了对神经元数量下降的怀疑，通过正常衰老过程中的神经元死亡。如果缺乏显著的神经元损失，则可以在老年个体的脑中检测到神经变性的几种病理学特征，例如帕金森病的典型的路易体和阿尔茨海默病的典型的老年斑的存在。因此，从这些观察中提出的问题是，除了参与神经元死亡之外，细胞凋亡是否会影响正常衰老期间发生的认知过程的下降。半胱天冬酶是一个蛋白酶家族，在长期空间记忆存储中发挥关键作用。Caspase-1（IL-1b转换酶）具有通过IL-1b介导参与细胞凋亡和炎症激活的特性。研究表明，抑制caspase-1通过减少细胞凋亡和减少促炎性细胞因子诱导脑缺血神经保护作用。虽然白细胞介素-1b在神经退行性疾病中高度表达，参与认知障碍，并诱导神经胶质细胞培养中的细胞死亡，但IL-1b和caspase是否相互作用以表达其对学习和记忆的影响，仍然是未知的。

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.