A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (App^G-F mice) to avoid potential deleterious effects of the Swedish mutation and generated App^G-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, the introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE 4 carriers.

先前在北欧进行的一项流行病学研究表明，淀粉样蛋白前体蛋白基因 （APP） 中的 A673T 突变（冰岛突变）可以预防阿尔茨海默病 （AD）。虽然 A673T 突变对 APP 加工的影响主要在体外进行了研究，但尚未评估其体内影响。这主要是因为大多数现有的 AD 小鼠模型都携带瑞典突变。瑞典突变和冰岛突变都位于 β 切割位点附近，并且假定每个突变对 β 切割具有相反的影响。因此，在具有瑞典突变的 AD 小鼠模型中，其效果可以与冰岛突变的效果竞争。在这里，我们将 A673T 突变引入没有瑞典突变的 App 敲入小鼠（App^G-F 小鼠）中，以避免瑞典突变和生成的 App^G-F-A673T 小鼠的潜在有害影响。APP-A673T 显着下调这些动物大脑中 β 裂解并减弱 Aβ 和淀粉样蛋白病理的产生。冰岛突变还减少了神经炎症和神经炎改变。对两性都进行了研究。这是冰岛突变对体内淀粉样蛋白病理保护作用的首次成功证明。我们的研究结果表明，特异性抑制 APP-BACE1 相互作用可能是一种很有前途的治疗方法。或者，使用体内基因组编辑技术引入疾病保护性突变（如 APP-A673T）可能是针对 AD 高危个体（如家族性 AD 基因突变携带者和 APOE 4 携带者）的新型治疗方法。