The inflammatory mechanisms underlying olfactory dysfunction in prognosis of TBI progression to dementia

嗅觉功能障碍的炎症机制在 TBI 进展为痴呆的预后中的作用

• 批准号: 10645083
• 负责人: Shaolin Liu
• 金额: $ 63.11万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645083
• 关键词: Ablation; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Anosmia; Atrophic; Behavior; Biochemical; Cells; Chronic; Clinical; Clinical Research; Cognitive; Cognitive deficits; Data; Dementia; Development; Diagnosis; Disease Management; Disease Progression; Early Diagnosis; Early identification; Electrophysiology (science); Exhibits; Functional disorder; Future; Generations; Genetic; Hippocampus; Impairment; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Ion Channel; Knockout Mice; Link; Literature; Mediating; Medical; Microglia; Microscopy; Modeling; Molecular; Mus; NADPH Oxidase; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurons; Olfactory Pathways; Olfactory dysfunction; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Population; Positioning Attribute; Prevention; Prognosis; Quality of life; Reactive Oxygen Species; Recording of previous events; Research; Risk; Risk Factors; Role; Sensory Disorders; Severity of illness; Signal Transduction; Structure; Survivors; Symptoms; Synapses; TBI Patients; Therapeutic; Therapeutic Effect; Trauma; Traumatic Brain Injury; accurate diagnosis; behavioral impairment; controlled cortical impact; cytokine; designer receptors exclusively activated by designer drugs; early detection biomarkers; effective therapy; epidemiology study; experimental study; functional improvement; functional outcomes; glial activation; hyperphosphorylated tau; in vivo; inhibitor; interdisciplinary approach; network dysfunction; neurobehavioral test; neuroinflammation; neuronal excitability; neuropathology; neuropsychiatry; neurotoxic; olfactory bulb; operation; pharmacologic; piriform cortex; prodromal Alzheimer' s disease; synaptic function; tau-1; treatment strategy

Project Summary 20–68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but also cognitive and neuropsychiatric functions. Although post- traumatic anosmia has been documented in the medical literature for more than a century, neither the underlying mechanisms nor treatment remain clear. Moreover, the occurrence of TBI significantly increases risk for the development of Alzheimer’s disease (AD) or non-AD forms of dementia. Recent studies of OD have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. AD pathogenesis revealed that the peripheral olfactory pathways including the olfactory bulb (OB) are the potential structural candidates responsible for OD in prodromal AD. Emerging studies have associated OD with the presence of OB inflammatory response, suggesting that OB pathology may provide a mechanistic link between TBI and AD or dementia. Recent data indicate that TBI-induced rapid and persistent pro-inflammatory responses in the OB were accompanied by increased phosphorylated tau and OB atrophy, resulting in early and persistent olfactory deficits. New data indicate that microglia-mediated inflammation contributed to neuronal hyperexcitation in the OB which was mitigated in the absence of Hv1, a newly discovered microglial ion channel required for NADPH oxidase-dependent generation of reactive oxygen species. Based on these findings and our preliminary data, we hypothesize that early after TBI microglial Hv1-mediated inflammation in the OB contributes to hyperexcitation of local neurons leading to olfactory dysfunction, thus heralding its progression to late-onset neurodegeneration. With multidisciplinary approaches including the Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic inhibition of OB microglia, microglia-specific and inducible Hv1 KO mice combined with microscopy and biochemical approaches, and comprehensive neurobehavioral testing, we will examine neuroinflammation and neurodegeneration in the OB in a well-established controlled cortical impact mouse TBI model and their correlation with OD and late-onset dementia-like behaviors (AIM 1). Furthermore, powerful in vivo and in vitro electrophysiological approaches will be applied to characterize detrimental effects of TBI-induced inflammation on network and synaptic functions in the OB (AIM 2). Lastly, we will determine whether genetic or pharmacological inhibition of inflammatory pathways in the OB through intranasal delivery mitigates TBI-induced inflammation and neurodegeneration thus improves functional outcomes (AIM 3). Our study will be the first to link olfactory dysfunction to dementia and neurodegeneration following TBI. Our findings will potentially shed light on developing effective approaches for early and accurate diagnosis of TBI-associated OD in the development of neurodegeneration and dementia.

项目摘要 20-68%的创伤性脑损伤（TBI）患者表现出创伤相关的嗅觉缺陷（OD）， 不仅危及生活质量，还危及认知和神经精神功能。虽然后- 创伤性嗅觉丧失在医学文献中已有超过世纪的记载， 潜在的机制和治疗方法仍不清楚。此外，TBI的发生率显著增加 阿尔茨海默病（AD）或非AD形式的痴呆的发展风险。最近的研究表明， 将其作为神经退行性疾病及其疾病诊断的早期生物标志物的潜力 进展因此，创伤性脑损伤幸存者OD可能是其进展为痴呆的早期征兆。AD 发病机制表明，包括嗅球（OB）在内的外周嗅觉通路是潜在的 负责前驱AD中OD的结构候选物。新兴的研究将OD与 OB炎症反应的存在，表明OB病理学可能提供了一个机械联系， TBI和AD或痴呆。最近的数据表明，TBI诱导的快速和持续的促炎症反应， OB中的反应伴随着磷酸化tau蛋白的增加和OB萎缩，导致早期 和持续的嗅觉缺陷新的数据表明，小胶质细胞介导的炎症有助于 OB中的神经元过度兴奋，在没有Hv 1（一种新发现的小胶质细胞）的情况下减轻 NADPH氧化酶依赖性产生活性氧所需离子通道。基于这些 研究结果和我们的初步数据，我们假设TBI后早期小胶质细胞Hv 1介导的炎症， OB有助于局部神经元的过度兴奋，导致嗅觉功能障碍，从而预示着其 进展为迟发性神经变性 通过多学科方法，包括设计师专用的设计师受体 基于药物（DREADD）的OB小胶质细胞化学发生抑制，小胶质细胞特异性和诱导性Hv 1 KO 结合显微镜和生化方法以及全面的神经行为测试， 将检查OB中的神经炎症和神经退行性病变， 影响小鼠TBI模型及其与OD和迟发性痴呆样行为（AIM 1）相关性。 此外，强大的体内和体外电生理方法将被应用于表征 TBI诱导的炎症对OB中网络和突触功能的有害影响（AIM 2）。最后， 我们将确定是否通过基因或药理学抑制OB中的炎症通路， 鼻内递送减轻TBI诱导的炎症和神经变性，从而改善功能性 目标3（AIM 3）。 我们的研究将是第一个将嗅觉功能障碍与TBI后的痴呆和神经变性联系起来的研究。 我们的研究结果可能有助于开发早期和准确诊断的有效方法， TBI相关OD在神经变性和痴呆发展中的作用