Journal Article

FZJ-2021-05883

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation

Pagnon de la Vega, M. ; Giedraitis, V. ; Michno, W. ; Kilander, L. ; Güner, G. ; Zielinski, M.FZJ* ; Löwenmark, M. ; Brundin, R. ; Danfors, T. ; Söderberg, L. ; Alafuzoff, I. ; Nilsson, L. N. G. ; Erlandsson, A. ; Willbold, D.FZJ* ; Müller, S. A. ; Schröder, G. F.FZJ* ; Hanrieder, J. ; Lichtenthaler, S. F. ; Lannfelt, L. ; Sehlin, D. ; Ingelsson, M. (Corresponding author)

2021
AAAS Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/33781  doi:10.1126/scitranslmed.abc6184

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 sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected by amyloid-positron emission tomography. 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.

Note: ERRATUM: In the Research Article “The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid-β fibril formation”, Figure 1A shows incorrect labelling of the three patients and Figure 1C does not display the correct transversal FDG-PET image for patient 3. These errors have been corrected. Line 4 of the abstract included an incorrect statement and this has been revised to read: “Symptoms and biomarkers are typical of sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected with amyloid-positron emission tomography”. On page 4, left column, the text discussing Figure 4C was imprecise and has been revised to read: “The amounts of Aβwt1–40 and Aβwt1–42 in CSF, produced from the nonmutated APP allele, were lower in patients with the Uppsala APP mutation compared to healthy control subjects. In addition, the amount of Aβwt1–40 in the CSF of patients with the mutation was lower than in sAD cases (Fig. 4C).” The online PDF and HTML (full text) have been updated. These corrections do not impact the interpretation of the data or the conclusions of the paper.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2021

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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