The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.
AD
Aβ
PALP
PSEN1
familial Alzheimer's disease
iPSC
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
02 Jun 2024
02 Jun 2024
Historique:
revised:
22
04
2024
received:
07
12
2023
accepted:
24
04
2024
medline:
2
6
2024
pubmed:
2
6
2024
entrez:
2
6
2024
Statut:
aheadofprint
Résumé
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 heterogeneity will enhance our understanding of the mechanisms of AD more widely. To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). 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 post-mortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired. 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. PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aβ43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Alzheimer's Society fellowship
ID : AS-JF-18-008
Organisme : Alzheimer's Research UK
ID : ARUK-SRF2016B-2
Organisme : EMBO scientific exchange
ID : 9297
Organisme : The Sigrid Rausing Trust
Organisme : Association of Frontotemporal Dementia
Organisme : UK Dementia Research Institute
ID : UKDRI-1014
Organisme : UK Medical Research Council
Organisme : University of London Chadburn Academic Clinical Lectureship
Organisme : Medical Research Council
ID : MR/M02492X/1
Pays : United Kingdom
Organisme : Alzheimer's Society and ARUK
Organisme : National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre
Informations de copyright
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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