Neuroinflammation is a key contributor to the pathology of Alzheimer’s Disease (ad). CD33 (Siglec-3) is a transmembrane sialic acid-binding receptor on the surface of microglial cells. CD33 is upregulated on microglial cells from post-mortem ad patient brains and high levels of CD33 inhibit uptake and clearance of amyloid beta (Aβ) in microglial cell cultures. Furthermore, knock-out of CD33 reduces amyloid plaque burden in mouse models of ad. Here, we tested whether a gene therapy strategy to reduce CD33 on microglia in ad could decrease Aβ plaque load. Intracerebroventricular injection of an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miR^CD33) into APP/PS1 mice reduced CD33 mRNA and TBS-soluble Aβ40 and Aβ42 levels in brain extracts. Treatment of APP/PS1 mice with miR^CD33 vector at an early age (2 months) was more effective at reducing Aβ plaque burden than intervening at later times (8 months). Furthermore, early intervention downregulated several microglial receptor transcripts (e.g. CD11c, CD47 and CD36) and pro-inflammatory activation genes (e.g. Tlr4 and Il1b). Marked reductions in the chemokine Ccl2 and the pro-inflammatory cytokine Tnfα were observed at the protein level in the brain from APP/PS1 mice treated with miR^CD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knock-down strategies to reduce ad pathology.

中文翻译：

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靶向 CD33 的阿尔茨海默病基因疗法可减少淀粉样蛋白 β 的积累和神经炎症。

神经炎症是阿尔茨海默病 ( ad )病理学的关键促成因素。CD33 (Siglec-3) 是小胶质细胞表面的跨膜唾液酸结合受体。CD33从验尸上调对小胶质细胞的广告病人的大脑和高水平的小胶质细胞培养物CD33抑制吸收和β淀粉样蛋白（Aβ）的清除。此外，敲除CD33可减少ad小鼠模型中的淀粉样蛋白斑块负担。在这里，我们测试了减少广告中小胶质细胞上CD33的基因治疗策略是否可以减少 Aβ 斑块负荷。基于腺相关病毒 (AAV) 载体的系统的脑室内注射编码人工微 RNA 靶向CD33 (miR ^CD33 ) 进入APP/PS1小鼠会降低脑提取物中的CD33 mRNA 和 TBS 可溶性 Aβ40 和 Aβ42 水平。在早期（2 个月）用 miR ^CD33载体治疗APP/PS1小鼠在减少 Aβ 斑块负担方面比在后期（8 个月）进行干预更有效。此外，早期干预下调了几种小胶质细胞受体转录物（例如CD11c、CD47和CD36）和促炎激活基因（例如Tlr4和Il1b）。在用 miR ^CD33载体处理的APP/PS1小鼠的大脑中，在蛋白质水平上观察到趋化因子 Ccl2 和促炎细胞因子 Tnfα 的显着减少。总体而言，我们的数据表明 CD33 是基于 AAV 的击倒策略以减少广告病理的可行目标。