Linking Olfactory deficits to Neurodegenerative Disorders

项目摘要 胆碱能神经支配的丧失是许多神经退行性疾病的早期病理标志， 阿尔茨海默病（AD）和帕金森病（PD），并且它被认为是认知缺陷的基础， 这些疾病。另一个早期症状，在这些疾病的典型症状之前， 多年来，他一直缺乏嗅觉。如果我们能提供一个机械的解释 将这些早期缺陷与AD和PD联系起来，我们将有这些疾病的早期生物标志物，并允许 制定早期干预和治疗战略。 在这个建议中，我们测试的想法，嗅觉侮辱可以导致中枢神经元的退化 它们表达的基因赋予了退化的易感性。为了验证这个想法，我们将使用小鼠模型 只在胆碱能神经元中过度表达这些基因。正在测试的两个基因是tau， 与AD（以及现在的PD）和A53 T突变体α突触核蛋白（A53 T αsyn）沿着荧光团有关 (GFP或TD-Tomato）。 小鼠将经受化学诱导的嗅觉丧失或特异性靶向治疗。 嗅球中的多巴胺能神经元（鼻内MPTP或立体定向注射的6-OHDA）。 然后我们将检查这些小鼠的胆碱能投射。为此，我们将使用 一种使大脑透明的技术，加上光片显微镜，使我们能够成像， 深入组织使用这种技术，我们将重建和呈现在3-D的胆碱能神经支配， 基底前脑到嗅球这将使我们能够比较胆碱能神经支配的变化 在嗅觉刺激的情况下 这个项目是第一次尝试提供嗅觉功能障碍和认知功能障碍之间的联系。 AD和PD中出现的症状。它也将是第一个提供详细的3D渲染的基础 前脑胆碱能系统这项研究的结果将为使用嗅觉功能障碍作为 神经退行性疾病的早期生物标志物。

Project Summary Loss of cholinergic innervation is an early pathological sign in many neurodegenerative disease like Alzheimer's disease (AD) and Parkinson's disease (PD) and it is thought to underlie cognitive deficits in these diseases. Another early symptom, one that precedes the canonical symptoms of these diseases by many years is deficits in olfaction. It stands to reason that if we can provide a mechanistic explanation linking these early deficits to AD and PD, we will have an early biomarker for these diseases and allow for the design of strategies for early intervention and treatment. In this proposal we test the idea that olfactory insults can cause the degeneration of central neurons that express genes that confer susceptibility to degeneration. To test this idea, we will use mouse models that over-express these genes only in cholinergic neurons. The two genes being tested are the tau, implicated in AD (and now in PD) and the A53T mutant α synuclein (A53T αsyn) along with a flurophore (GFP or Td-Tomato). The mice will be subject to either chemically-induced anosmia or treatments that specifically target dopaminergic neurons in the olfactory bulb (intranasal MPTP or stereotactically injected 6-OHDA). We will then examine the cholinergic projections in these mice. For this we will use the CLARITY technique for rendering the brain transparent coupled with light sheet microscopy that allows us to image deep into tissues. Using this technique we will reconstruct and render in 3-D the cholinergic innervation from the basal forebrain to the olfactory bulb. This will allow us to compare changes in cholinergic innervation under conditions of olfactory insults. This project is the first attempt at providing a link between olfactory dysfunction and the cognitive symptoms seen in AD and PD. It will also be the first to provide a detailed 3-D rendering of the basal forebrain cholinergic system. Results from this study will provide the basis for using olfactory dysfunction as an early biomarker for neurodegenerative diseases.