Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta

Arber, C. (author)

Toombs, J. (author)

Lovejoy, C. C. (author)

Ryan, N. S. (author)

Paterson, R. W. (author)

Willumsen, N. (author)

Gkanatsiou, Eleni (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Portelius, Erik, 1977 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Blennow, Kaj, 1958 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Heslegrave, A. (author)

Schott, J. M. (author)

Hardy, J. (author)

Lashley, T. (author)

Fox, N. C. (author)

Zetterberg, Henrik, 1973 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Wray, S. (author)

(creator_code:org_t)

2019-04-12
2020
English.
In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:11, s. 2919-2931

Related links:: https://www.nature.c...; show more...; https://gup.ub.gu.se...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: Arber, C.; Toombs, J.; Lovejoy, C. C.; Ryan, N. S.; Paterson, R. W.; Willumsen, N.; show more...; Gkanatsiou, Elen ...; Portelius, Erik, ...; Blennow, Kaj, 19 ...; Heslegrave, A.; Schott, J. M.; Hardy, J.; Lashley, T.; Fox, N. C.; Zetterberg, Henr ...; Wray, S.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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