Pagnon de la Vega M, Giedraitis V, Michno W, Kilander L, Güner G, Zielinski M, Löwenmark M, Brundin R, Danfors T, Söderberg L, Alafuzoff I, Nilsson LNG, Erlandsson A, Willbold D, Müller SA, Schröder GF, Hanrieder J, Lichtenthaler SF, Lannfelt L, Sehlin D, Ingelsson M
Sci Transl Med 13 (606) - [2021-08-11; online 2021-08-13]
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.