Petit, Dieter;
Fernández, Sara Gutiérrez;
Zoltowska, Katarzyna Marta;
Enzlein, Thomas;
Ryan, Natalie S;
O'Connor, Antoinette;
Szaruga, Maria;
... Chávez-Gutiérrez, Lucía; + view all
(2022)
Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.
Molecular Psychiatry
10.1038/s41380-022-01518-6.
(In press).
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Abstract
Familial Alzheimer’s disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of ‘unclear’ PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides.
| Type: | Article |
|---|---|
| Title: | Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41380-022-01518-6 |
| Publisher version: | https://doi.org/10.1038/s41380-022-01518-6 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10146632 |
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