The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations
Date
2024
Authors
Arber, C.
Belder, C.R.S.
Tomczuk, F.
Gabriele, R.
Buhidma, Y.
Farrell, C.
O'Connor, A.
Rice, H.
Lashley, T.
Fox, N.C.
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Journal article
Citation
Alzheimer's and Dementia, 2024; 20(7):4717-4726
Statement of Responsibility
Charles Arber, Christopher R. S. Belder, Filip Tomczuk, Rebecca Gabriele, Yazead Buhidma, Clíona Farrell, Antoinette O, Connor, Helen Rice, Tammaryn Lashley, Nick C. Fox, Natalie S. Ryan, SelinaWray
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Abstract
INTRODUCTION: Familial Alzheimer’s disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneitywill enhance our understanding of themechanisms of AD more widely. METHODS:To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals,withmagnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). RESULTS: An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and postmortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired. DISCUSSION:We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation.
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©2024 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.