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- Title
The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation.
- Authors
Pagnon de la Vega, María; Giedraitis, Vilmantas; Michno, Wojciech; Kilander, Lena; Güner, Gökhan; Zielinski, Mara; Löwenmark, Malin; Brundin, RoseMarie; Danfors, Torsten; Söderberg, Linda; Alafuzoff, Irina; Nilsson, Lars N.G.; Erlandsson, Anna; Willbold, Dieter; Müller, Stephan A.; Schröder, Gunnar F.; Hanrieder, Jörg; Lichtenthaler, Stefan F.; Lannfelt, Lars; Sehlin, Dag
- Abstract
APP from Sweden: The amyloid precursor protein (APP) gene encodes amyloid precursor protein, whose proteolysis gives rise to Aβ peptides. Mutations in APP cause familial Alzheimer's disease (AD). In this study, Pagnon de la Vega et al. describe a pathogenic APP deletion causing a dominant form of AD. This mutation, called the UppsalaAPP mutation, results in early onset, fast-progressing AD. At molecular level, the Uppsala APP mutation alters the protein processing, resulting in increased Aβ production and rapid aggregation. The results contribute to elucidate the molecular mechanisms regulating AD development and to understand the impact of APP mutations on disease pathophysiology. 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, AβUpp1–42Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 606, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abc6184