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- Arber, C., et al.
(author)
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Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta
- 2020
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:11, s. 2919-2931
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Journal article (peer-reviewed)abstract
- Familial Alzheimer’s disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD. © 2019, Springer Nature Limited.
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| 2. |
- Gkanatsiou, Eleni
(author)
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Revealing the complex nature of amyloid beta and its relation to dementia
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer disease (AD) is the most common type of dementia and characterized by the accumulation of amyloid plaques in the extracellular space of the brain parenchyma. Amyloid plaques consist of amyloid beta peptides (Aβ). Amyloid pathology can also be involved in other types of dementia, either as a driving force or as a coexisting pathology. In this thesis was the Aβ peptide content in relation to different amyloid deposits, types of dementia and regions investigated with the goal to improve our understanding of amyloid pathology in dementia. To analyse Aβ peptides, a hybrid immunoprecipitation - mass spectrometry method was used. The studies presented here reveal a different Aβ peptide pattern in individuals with amyloid pathology, but cognitively unaffected, compared with AD patients, who suffer from cognitive decline. Moreover, vascular Aβ contribution, due to cerebral amyloid angiopathy, differs from amyloid plaque Aβ contribution. For other groups with plaque pathology, such as Down syndrome, dementia with Lewy bodies, and Parkinson’s disease dementia, there are minor differences in the Aβ peptide pattern compared with AD. In this work, the Aβ content of the protofibril/oligomeric forms, a major anti-amyloid therapeutical target, is also revealed. This thesis can be the beginning of a deeper understanding of the complex nature of amyloid pathology and its contribution to dementia.
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