The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aß43 and atypical clinical manifestations.
Alzheimers Dement
; 20(7): 4717-4726, 2024 07.
Article
em En
| MEDLINE
| ID: mdl-38824433
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 heterogeneity will enhance our understanding of the mechanisms of AD more widely.METHODS:
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).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 post-mortem tissue supported high production of amyloid beta 43 (Aß43). 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. HIGHLIGHTS 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 (Aß43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Presenilina-1
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Células-Tronco Pluripotentes Induzidas
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Doença de Alzheimer
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Mutação
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article