The pathology of familial Alzheimer’s disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR–Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood–brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer’s disease and other monogenic diseases that affect multiple brain regions.

家族性阿尔茨海默病的病理学是由编码淀粉样β前体蛋白 (APP) 的基因和编码早老素 1 和早老素 2 的基因的显性突变引起的，其特征是多脑中的细胞外淀粉样斑块和细胞内神经原纤维缠结地区。在这里，我们展示了携带人类APP的转基因小鼠模型中突变的APP等位基因的全脑选择性破坏在单次海马内施用编码 Cas9 和靶向突变的单向导 RNA 的腺相关病毒后，瑞典突变缓解了与淀粉样蛋白-β 相关的病理至少六个月。我们还表明，当 CRISPR-Cas9 构建体通过可以穿过血液的改良腺相关病毒静脉内递送时，β-淀粉样蛋白的沉积以及小胶质细胞增生、神经突营养不良和认知能力障碍都可以得到改善——脑屏障。全脑疾病修饰基因组编辑可以代表治疗家族性阿尔茨海默病和其他影响多个大脑区域的单基因疾病的可行策略。