Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aβ42 and only slightly pathological amyloid–positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1–42_Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

淀粉样前体蛋白基因 ( APP ) 的点突变通过增加淀粉样蛋白 β (Aβ) 的生成或改变构象而导致家族性阿尔茨海默病 (AD)。在这里，我们描述了Uppsala APP突变（Δ690-695），这是第一个报道的导致常染色体显性 AD 的缺失。受影响的个体的症状出现年龄在四十出头，并且患有快速进展的疾病过程。症状和生物标志物是 AD 的典型特征，除了正常的脑脊液 (CSF) Aβ42 和只有轻微的病理性淀粉样蛋白 - 正电子发射断层扫描信号。来自实验细胞培养物的患者脑脊液和培养基的质谱和蛋白质印迹分析表明，乌普萨拉 APP突变通过增加 β-分泌酶切割和影响 α-分泌酶切割来改变 APP 加工。此外，对患者脑组织样本的体外聚集研究和分析表明，较长形式的突变 Aβ，AβUpp1-42 _Δ19-24，加速了具有独特多晶型的原纤维的形成以及它们在受影响大脑中沉积到淀粉样蛋白斑块中。