Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants-TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1-potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

中文翻译：

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通往阿尔茨海默氏病神经炎症机制的精准医学之路。

神经炎症开始于阿尔茨海默氏病（AD）临床发作之前的几十年，是整个AD连续体中最早的病理机制改变之一。大规模的全基因组关联研究指出了可能与神经炎症相关的几种遗传变异-TREM2，CD33，PILRA，CR1，MS4A，CLU，ABCA7，EPHA1和HLA-DRB5-HLA-DRB1。这些基因大多数参与促炎性细胞内信号转导，细胞因子/白介素/细胞更新，突触活性，脂质代谢和囊泡运输。蛋白质组学研究表明，由TNF-α，TGF-β，IL-1β和受体蛋白TREM2引起并持久存在的大量相互联系的异常分子途径与神经炎症有关。小胶质细胞和星形胶质细胞是神经炎症的关键细胞驱动器和调节剂。在生理条件下，它们对于神经传递和突触体内平衡很重要。在AD中，在其整个病理生理学演变中存在一个转折点，其中神经胶质细胞维持过度表达的炎症反应，该炎症反应与淀粉样蛋白β和tau的积累协同作用，并以自我增强的方式驱动突触毒性和神经变性。尽管有很强的治疗学原理，但以前的具有抗炎特性的化合物，包括非甾体类抗炎药（NSAIDs）的临床研究仍未达到主要疗效终点。可以想象，研究设计问题，包括缺乏诊断准确性和目标人群识别的生物标志物以及机制的证明，可能部分解释了负面结果。然而，最近的荟萃分析表明非甾体抗炎药具有潜在的生物学作用。在这方面，神经炎症的候选体液生物标志物正在分析/临床验证中，即TREM2，IL-1β，MCP-1，IL-6，TNF-α受体复合物，TGF-β和YKL-40。对PET放射性配体进行了研究，以完成体内和纵向区域神经炎症的探索。追踪不同分子途径（体液基质）以及脑神经炎症内表型（神经影像标记）的生物标志物可以使神经炎症与其他AD病理生理机制之间的时空动态发生纠缠。健壮的生物标志物-药物联合开发管道有望丰富直接或间接活性新一代化合物测试的大规模临床试验，神经炎性靶标并显示出推定的疾病改善作用：新型NSAID，AL002（抗TREM2抗体），抗Aβ原纤维（BAN2401）和AL003（抗CD33抗体）。下一步，利用突破性和多模式技术与系统生物学方法相结合，是在精密医学的框架下开发针对神经炎症的个性化治疗策略的途径。