Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, Cornell University, New York, New York, USA,
Gerontology. 2019;65(4):323-331. doi: 10.1159/000492596. Epub 2018 Dec 12.
Alzheimer's disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.
阿尔茨海默病（AD）影响着全球近 5000 万人，目前尚无针对该病的治疗方法。由于抗淀粉样蛋白-β或tau 为基础的疗法不断失败，因此确定新的靶点成为 AD 预防和治疗的当务之急。最近，传统的遗传方法和计算策略都集中在免疫炎症途径上，认为这些途径是 AD 发病机制中的关键事件。许多基因与晚发性散发性 AD 的发病和发展高度相关，AD 是最常见的形式。引人注目的是，这些基因中的大多数都与小胶质细胞生物学有关。小胶质细胞受体（如 TREM2、CD33 和 CR3）的突变和/或差异表达与 AD 发病风险的增加密切相关。自这些风险因素被确定以来，它们在 AD 发病机制中的作用机制一直受到积极研究。这些基因是否可以作为一种疾病修饰治疗的靶点仍存在争议。CD33 是全基因组关联研究确定的 AD 风险最高的基因之一。这篇综述总结了 CD33 的最新生物学进展及其与 AD 的关联。它还从药物发现的角度提供了对 CD33 的可药性、治疗策略以及将其作为治疗这种破坏性疾病的靶点的挑战的见解。
