The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation

María Pagnon De la Vega, Vilmantas Giedraitis, Wojciech Michno, Lena Kilander, Gökhan Güner, Mara Zielinski, Malin Löwenmark, Rose Marie Brundin, Torsten Danfors, Linda Söderberg, Irina Alafuzoff, Lars N.G. Nilsson, Anna Erlandsson, Dieter Willbold, Stephan A. Müller, Gunnar F. Schröder, Jörg Hanrieder, Stefan F. Lichtenthaler, Lars Lannfelt, Dag SehlinMartin Ingelsson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereabc6184
JournalScience Translational Medicine
Volume13
Issue number606
DOIs
StatePublished - 11 Aug 2021
Externally publishedYes

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