Huynh Tien-Phat V, Liao Fan, Francis Caroline M, Robinson Grace O, Serrano Javier Remolina, Jiang Hong, Roh Joseph, Finn Mary Beth, Sullivan Patrick M, Esparza Thomas J, Stewart Floy R, Mahan Thomas E, Ulrich Jason D, Cole Tracy, Holtzman David M
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Neuron. 2017 Dec 6;96(5):1013-1023.e4. doi: 10.1016/j.neuron.2017.11.014.
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.
载脂蛋白E（APOE）基因是晚发性阿尔茨海默病最强的遗传风险因素。先前的研究表明，通过基因操作降低载脂蛋白E水平可减少β淀粉样蛋白（Aβ）病理改变。然而，出生后载脂蛋白E水平降低如何影响淀粉样蛋白沉积尚不清楚。我们利用反义寡核苷酸（ASO）降低携带APOE-ε4或APOE-ε3等位基因纯合子的APP/PS1-21小鼠大脑中的载脂蛋白E表达。出生后开始的ASO治疗在4个月时评估导致Aβ病理显著减少。有趣的是，在淀粉样蛋白沉积开始时开始的ASO治疗导致Aβ斑块大小增加和斑块相关神经纤维营养不良减少，而总斑块负荷没有变化。这些结果表明，在斑块沉积之前降低载脂蛋白E水平可强烈影响Aβ病理的起始，而在Aβ播种后降低载脂蛋白E则可调节斑块大小和毒性。
