nbInnate Immunity Responses In Monocytes: Contribution To Neurodegeneration

单核细胞先天免疫反应障碍与神经退行性变的关系 摘要 阿尔茨海默病(AD)是主要原因，其特征是β-淀粉样蛋白(Aβ40和Aβ42)水平升高 痴呆症的发病率，在全世界大约12%的人口中流行。反过来，与艾滋病毒相关的 神经认知障碍(手)在20%-50%的艾滋病毒携带者(PWH)1，2中普遍存在，尽管有机会 联合抗逆转录病毒疗法(CART)。单核细胞募集到脑内促进巨噬细胞吞噬 Aβ斑块的清除和中枢神经系统(CNS)内稳态的恢复(文献3回顾)。 然而，在HIV感染中，外周血单核细胞渗透到受损的血脑屏障(BBB)中 中枢神经系统，触发炎症和神经元损伤4-7。有趣的是，手部患者表现出积聚的 血液和大脑9-12中的β，尽管存在渗透的单核细胞。HIV劫持其目标细胞 通过削弱I型干扰素(干扰素-1)信号来促进病毒复制。在AD中，改变了干扰素-1 反应减少单核细胞对CNS15的募集。干扰素-1信号损害胰岛素的产生 18，胰岛素信号转导失调加剧Aβ斑块形成19，20。反过来，Aβ水平升高 导致胰岛素抵抗和认知功能下降21。在服用CART的HIV患者中，胰岛素抵抗的发生率 与健康的人相比更高，这反过来又与更糟糕的神经心理有关 表现，这表明代谢改变也可能有助于HAND22，23的发展。 因此，Aβ代谢、胰岛素信号和认知障碍是相互关联的。由于他们的不同 病因，AD病理和HIV神经发病的共同机制并不是很好 明白了。我推测，单核/巨噬细胞(MφS)干扰素-1信号受损改变了它们的 表型和胰岛素受体(IR)代谢，导致手部和AD的认知障碍 病人。在这项研究中，我将确定MφS干扰素-1反应对认知功能下降的贡献，通过 目的如下：1)人单核细胞干扰素-1信号转导和胰岛素受体生物学特性 AD和手部患者的血液，按认知状态分层；2)使用脑器官模型我将确定 单核细胞在HIV感染时是神经保护性还是神经炎性，使用HIV阴性和 3)检测干扰素-1受体调控对M-φS表型的影响(S)， 以及使用脑器官的体外神经元功能障碍。这项研究的结果将揭示新的机制 参与神经退行性疾病外周和中枢神经系统之间的串扰。此外，我们的结果 将有助于确定针对认知障碍的有效治疗方法的候选对象和/或目标 手和手的数量都在下降。拟议的培训计划是为了利用我在细胞生物学方面的专业知识而量身定做的 和病毒免疫学，并用新的3D脑器官方法学扩大我的技能范围。这个 多学科指导团队致力于提供职业指导，丰富我对新知识的认识 技术，并确保我在学术界过渡到独立，专门从事神经免疫学。

Disruption of Innate Immunity Responses in Monocytes: Contribution to Neurodegeneration ABSTRACT Alzheimer’s disease (AD), characterized by elevated levels of β-amyloid (Aβ40 and Aβ42), is the leading cause of dementia, prevailing in approximately 12% of the population worldwide. In turn, HIV-associated neurocognitive disorders (HAND) prevail in 20-50% of people with HIV (PWH)1,2, despite the access to combined antiretroviral therapy (cART). Monocyte recruitment to the brain promotes macrophage phagocytic clearance of Aβ plaques and restoration of central nervous system (CNS) homeostasis (reviewed in3). However, in HIV infection, peripheral monocytes infiltrate the compromised blood brain barrier (BBB) into the CNS, triggering inflammation and neuronal damage4–7. Interestingly, HAND patients exhibit accumulation of Aβ in the blood8 and in the brain9–12, despite the presence of infiltrated monocytes. HIV hijacks its target cells to promote viral replication by impairing the interferon type I (IFN-1) signaling13,14. In AD, altered IFN-1 response decreases the recruitment of monocytes to the CNS15. IFN-1 signaling impairs insulin production16– 18, and dysregulated insulin signaling exacerbates Aβ plaque formation19,20. In turn, elevated levels of Aβ contribute to insulin resistance and cognitive decline21. In HIV patients on cART, insulin resistance prevalence is higher, compared to healthy individuals, which in turn is associated with worse neuropsychological performance, suggesting that metabolic alterations could also contribute to the development of HAND22,23. Thus, Aβ metabolism, insulin signaling, and cognitive impairment are interconnected. Due to their different etiologies, the shared mechanisms underlying AD pathology and HIV neuropathogenesis are not well understood. I hypothesize that impaired IFN-1 signaling in monocyte/macrophage (Mφs) alters their phenotype and insulin receptor (IR) metabolism, contributing to cognitive impairment in HAND and in AD patients. In this study, I will determine the contribution of the Mφs IFN-1 response to cognitive decline, through the following aims: 1) Characterization of IFN-1 signaling and insulin receptor biology in monocytes from the blood of AD and HAND patients, stratified by cognitive status; 2) using brain organoid models I will determine whether monocytes are neuroprotective or neuroinflammatory upon HIV infection, using HIV-negative and positive subjects’ monocytes; 3) I will determine the effect(s) of IFN-1 receptor modulation on Mφs phenotype, and neuronal dysfunction in vitro using brain organoids. Results from this study will uncover novel mechanisms involved in the crosstalk between the peripheral and CNS in neurodegenerative disorders. Further, our results will help identifying candidates and/or targets for the development of effective therapies against cognitive decline in HAND andAD. The proposed training plan is tailored to capitalize on my expertise in cellular biology and viral immunology, and to expand my skill set with novel 3D brain organoids methodologies. The multidisciplinary mentoring team is committed to provide career guidance, enrich my knowledge on new techniques, and ensure my transition to independence in academia, specializing in neuroimmunology.