Department of Neurobiology, University of Chicago, Chicago, IL.
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA.
J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20210313.
Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptide levels and acceleration of Aβ deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aβ production and deposition.
家族性阿尔茨海默病（FAD）相关的 APP 基因突变要么发生在 Aβ 编码区内部，要么就在其附近，位于外显子 16 和 17，这些外显子编码 Aβ 肽。我们已经在 APP 中鉴定出一种非常罕见的、部分外显的单核苷酸变异（SNV），rs145081708，它对应于外显子 5 中的 Ser198Pro 取代。我们现在报告称，在稳定转染的细胞中，携带 S198P 突变的 APP（APPS198P）的表达通过一种非传统的机制导致 Aβ 肽的产生增加，在这种机制中，APPS198P 从内质网的折叠和输出加速。更重要的是，在雄性和雌性转基因小鼠的大脑中，共表达 APP S198P 和 FAD 相关的 PS1ΔE9 变体导致 Aβ 肽水平的稳定状态升高，并加速 Aβ 沉积，与表达 APP 和 PS1ΔE9 的年龄和性别匹配的小鼠相比。这是 APP 中位于外显子 16 和 17 之外的第一个增强 Aβ 产生和沉积的 AD 相关突变。
