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| Title | The deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation. |
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| Journal, issue, pages | Sci Transl Med, Vol. 13, Issue 606, Year 2021 |
| Publish date | Aug 11, 2021 |
 Authors | María Pagnon de la Vega / Vilmantas Giedraitis / Wojciech Michno / Lena Kilander / Gökhan Güner / Mara Zielinski / Malin Löwenmark / RoseMarie 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 Sehlin / Martin Ingelsson /      |
| PubMed Abstract | Point mutations in the amyloid precursor protein gene () cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the mutation ...Point mutations in the amyloid precursor protein gene () cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the 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 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, AβUpp1-42, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain. |
 External links | Sci Transl Med / PubMed:34380771 |
| Methods | EM (helical sym.) |
| Resolution | 5.1 - 5.7 Å |
| Structure data |  EMDB-12592:  EMDB-12593: Amyloid-beta fibril of the Uppsala variant (polymorph 2) |
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Homo sapiens (human)