CoED5013 Innate Memory-related blood Biomarkers as a proxy of microglia-mediated neurodegeneration to predict early AD progression (ADIMB)

CoED5013 先天记忆相关的血液生物标志物作为小胶质细胞介导的神经变性的代表来预测早期 AD 进展 (ADIMB)

• 批准号: MR/V007688/1
• 负责人: Paul Edison
• 金额: $ 26.15万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV007688%2F1
• 关键词: CoED5013; Innate; Memory; related; blood

Alzheimer's disease (AD) is a severe and progressive illness of the brain. It is characterized by neuronal death and consequent impairment of memory, thinking and behavior. So far AD is incurable mainly because its diagnosis is based on symptoms developed because of the irreversible neuronal damage, thus too late for efficacious intervention. Recent studies suggest that inflammation in the brain, influenced by peripheral inflammatory conditions, is a main driver of this disease. The present research project will focus on patients with early AD and is addressed to evaluate changes in blood immune cells that are related to brain inflammation, early neuronal damage and severity of early symptoms. Our goal is to identify efficient blood tests to help diagnose AD and evaluate treatments. This result will be useful in making clinical trials more rigorous and affordable, will accelerate drug development and will improve clinical care by providing access to accurate diagnoses.Inflammation is a driving force in Alzheimer's disease (AD) and besides brain resident microglia, other innate immune cells from periphery, including dendritic cells (DCs), may have a role in AD pathogenesis and progression. Recent evidence indicates that following exposition to various stimuli, host innate immune cells undergo a mechanism of inflammation enhancement named innate memory (IM), which could contribute to neurodegeneration. DCs, a unique type of migratory innate immune cells that induce and regulate immune responses and inflammation, are subjected to IM reprogramming and orchestrate brain immune surveillance. In AD patients, DCs are dysfunctional and show pro-inflammatory profiles, thus when recruited to brain could contribute to neuropathology and promote neurodegeneration, reflecting the progression of disease. Aim of this project is to study AD patients at early disease stages in order to assess their blood levels of DCs as an index of cell recruitment to brain and define the IM status of their DCs in terms of enhanced inflammatory cytokine recall responses and epigenetic modifications following in vitro stimulations. The identified peripheral immune changes will be related to microglial activation, amyloid load and symptomatology to identify new peripheral biomarkers potentially helpful for diagnosis and disease progression tracking.

阿尔茨海默病（AD）是一种严重的进行性脑部疾病。它的特点是神经元死亡和随之而来的记忆、思维和行为障碍。到目前为止，AD是无法治愈的，主要是因为它的诊断是基于由于不可逆的神经元损伤而产生的症状，因此无法进行有效的干预。最近的研究表明，受外周炎症条件影响的大脑炎症是这种疾病的主要驱动因素。目前的研究项目将集中在早期AD患者身上，旨在评估与脑炎症、早期神经元损伤和早期症状严重程度相关的血液免疫细胞的变化。我们的目标是确定有效的血液检查来帮助诊断AD和评估治疗。这一结果将有助于使临床试验更加严格和负担得起，将加速药物开发，并将通过提供准确诊断来改善临床护理。炎症是阿尔茨海默病（AD）的一个驱动力，除了脑内小胶质细胞外，其他来自外周的先天免疫细胞，包括树突状细胞（dc），可能在AD的发病和进展中发挥作用。最近的证据表明，在暴露于各种刺激后，宿主先天免疫细胞会经历一种名为先天记忆（IM）的炎症增强机制，这可能导致神经退行性变。dc是一种独特的迁移性先天免疫细胞，可诱导和调节免疫反应和炎症，并受到IM重编程和协调脑免疫监视。在AD患者中，dc功能失调，并表现出促炎特征，因此当它们被招募到大脑时，可能会导致神经病理并促进神经退行性变，反映疾病的进展。该项目的目的是研究早期AD患者，以评估其血液dc水平作为细胞向大脑募集的指标，并根据体外刺激后炎症细胞因子回忆反应的增强和表观遗传修饰来确定其dc的IM状态。确定的外周免疫变化将与小胶质细胞激活、淀粉样蛋白负荷和症状学有关，以确定新的外周生物标志物，可能有助于诊断和疾病进展跟踪。

项目成果

Neuroinflammation is independently associated with brain network dysfunction in Alzheimer's disease.

• DOI: 10.1038/s41380-022-01878-z
• 发表时间: 2023-03
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Leng, Fangda;Hinz, Rainer;Gentleman, Steve;Hampshire, Adam;Dani, Melanie;Brooks, David J.;Edison, Paul
• 通讯作者: Edison, Paul