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

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

19 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummereabc6184
FachzeitschriftScience Translational Medicine
Jahrgang13
Ausgabenummer606
DOIs
PublikationsstatusVeröffentlicht - 11 Aug. 2021
Extern publiziertJa

Fingerprint

Untersuchen Sie die Forschungsthemen von „The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation“. Zusammen bilden sie einen einzigartigen Fingerprint.

Dieses zitieren