The Olfactory Bulb-Entorhinal Cortex Axis as an Early Biomarker for Alzheimers Disease

 描述(由申请人提供)：阿尔茨海默病(AD)的早期检测是抗击这种毁灭性疾病的关键因素。大脑退行性变和认知障碍的病理改变至少在痴呆发病前10-20年就开始了，这一发现为疾病诊断和治疗的改进提供了重要的靶点。开发生物标记物来检测与早期AD相关的神经病理将允许在病理过程中更早地实施预防性治疗，从而最大限度地提高治疗效果。值得注意的是，嗅觉障碍先于痴呆症和记忆力丧失的症状，这使得嗅觉测试成为早期AD检测的常用工具。由于嗅觉衰退也会发生在正常的衰老过程中，AD的准确诊断依赖于对这些过程的正确区分。有趣的是，众所周知，作为学习和记忆的关键途径，内嗅觉-海马体回路在AD患者中表现出早期的神经病理，并且嗅觉信息通过内嗅觉皮质传递到海马体。不幸的是，阿尔茨海默病和自然衰老的嗅觉缺陷的潜在机制仍然很大程度上是未知的。在这里，我们建议揭开嗅觉信息传递到内嗅觉皮质的机制，以及在自然衰老小鼠和AD转基因小鼠模型中嗅觉功能障碍之前的适应。为了实现这一目标，我们的研究团队将使用多学科方法，结合病毒辅助逆行标记、电生理学、光遗传学和行为评估。

 DESCRIPTION (provided by applicant): Early detection of Alzheimer's disease (AD) is a critical factor in combating this devastating disease. The discovery that pathological changes underlying brain degeneration and cognitive loss begin at least 10-20 years before dementia onset has provide an important target for the improvement of disease diagnosis and therapy. The development of biomarkers to detect neuropathology associated with early-stage AD will allow the implementation of preventive treatments much earlier in the pathological process, maximizing treatment efficacy. Notably, olfactory dysfunction precedes symptoms of dementia and memory loss, which has made olfactory tests a commonly used tool in early AD detection. As olfactory decline also occurs in normal aging, an accurate diagnosis of AD relies in the proper distinction between these processes. Interestingly, it is well established that the entorhinal-hippocampal circuit, a key pathway for learning and memory, exhibits early neuropathology in AD, and that olfactory information is relayed to the hippocampus via the entorhinal cortex. Unfortunately, the mechanisms underlying olfactory deficits in AD and natural aging remain largely unknown. Here we propose to unravel the mechanisms by which olfactory information is conveyed to the entorhinal cortex and the adaptations that precede olfactory dysfunction in naturally aging mice and in a transgenic mouse model of AD. To achieve this goal, our team of investigators will use a multidisciplinary approach that combines viral-assisted retrograde labeling, electrophysiology, optogenetics, and behavioral assessment.