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APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease
Molecular Therapy ( IF 12.4 ) Pub Date : 2024-03-19 , DOI: 10.1016/j.ymthe.2024.03.024
Rosemary J. Jackson , Megan S. Keiser , Jonah C. Meltzer , Dustin P. Fykstra , Steven E. Dierksmeier , Soroush Hajizadeh , Johannes Kreuzer , Robert Morris , Alexandra Melloni , Tsuneo Nakajima , Luis Tecedor , Paul T. Ranum , Ellie Carrell , YongHong Chen , Maryam A. Nishtar , David M. Holtzman , Wilhelm Haas , Beverly L. Davidson , Bradley T. Hyman

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

中文翻译:

APOE2 基因疗法可减少阿尔茨海默病小鼠模型中的淀粉样蛋白沉积并改善神经炎症和神经变性的标志物

流行病学研究表明,携带相对罕见的 APOE ε2 等位基因的个体很少患阿尔茨海默病,即使患上阿尔茨海默病,与不携带该等位基因的人相比,他们的发病年龄较晚,临床病程较轻,神经病理学结果也不那么严重。与阿尔茨海默病的主要遗传风险因素 APOE ε4 相比,这种对比尤其明显,该病的发病年龄早几十年,临床病程更具侵袭性,神经病理学结果更严重,特别是在淀粉样蛋白沉积量方面。在这里,我们证明,通过基因治疗方法将大脑暴露于 APOE ε2,在室管膜转导后将整个皮质套浸入基因产物中,减少 Aβ 斑块沉积、神经退行性突触损失,并且显着减少大脑中小胶质细胞的激活。尽管人 APOE ε4 持续表达,但 APP/PS1 小鼠模型。这一结果表明外源性 APOE ε2 具有良好的保护作用,并揭示了该蛋白对小胶质细胞激活的细胞非自主效应,我们发现这与遗传 APOE ε2 的阿尔茨海默病患者大脑中的斑块相关小胶质细胞相似。这些数据增加了 APOE ε2 疗法对阿尔茨海默病有效的潜力,即使对于出生时带有危险 ε4 等位基因的个体也是如此。
更新日期:2024-03-19
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