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Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation
Elsworthy RJ, King MC, Grainger A, Fisher E, Crowe JA, Alqattan S, Ludlam A, Hill DEJ et al.. Molecular and cellular neurosciences, 2021-05-20
Topic: Brain proteins, microglia and lab models
Introduction Presenilin-1 (PSEN1) gene mutations are the most common cause of familial Alzheimer's disease (fAD) and are known to interfere with activity of the membrane imbedded γ-secretase complex. PSEN1 mutations have been shown to shift Amyloid-β precursor protein (AβPP) processing toward amyloid-β (Aβ) 1-42 production. However, less is known about whether PSEN1 mutations may alter the activity of enzymes such as ADAM10, involved with non-amyloidogenic AβPP processing, and markers of oxidative stress. Materials and methods Control and PSEN1 mutation (L286V and R278I) Human Neural Stem Cells were spontaneously differentiated into neuron and astrocyte co-cultures. Cell lysates and culture media were collected and stored at -80 °C until further analysis. ADAM10 protein expression, the ratio of AβPP forms and Aβ1-42/40 were assessed. In addition, cellular redox status was quantified. Results The ratio of AβPP isoforms (130:110kDa) was significantly reduced in neuron and astrocyte co-cultures carrying PSEN1 gene mutations compared to control, and mature ADAM10 expression was lower in these cells. sAβPP-α was also significantly reduced in L286V mutation, but not in the R278I mutation cells. Both Aβ1-40 and Aβ1-42 were increased in conditioned cell media from L286V cells, however, this was not matched in R278I cells. The Aβ1-42:40 ratio was significantly elevated in R278I cells. Markers of protein carbonylation and lipid peroxidation were altered in both l286V and R278I mutations. Antioxidant status was significantly lower in R278I cells compared to control cells. Conclusions This data provides evidence that the PSEN1 mutations L286V and R278I significantly alter protein expression associated with AβPP processing and cellular redox status. In addition, this study highlights the potential for iPSC-derived neuron and astrocyte co-cultures to be used as an early human model of fAD.
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APA 7th
Elsworthy, R. J., King, M. C., Grainger, A., Fisher, E., Crowe, J. A., Alqattan, S., et al. (2021). Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation. Molecular and cellular neurosciences. https://doi.org/10.1016/j.mcn.2021.103631
Vancouver
Elsworthy RJ, King MC, Grainger A, Fisher E, Crowe JA, Alqattan S, et al. Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation. Molecular and cellular neurosciences. 2021. doi:10.1016/j.mcn.2021.103631. PMID: 34022327.
BibTeX
@article{elsworthy2021-34022327,
author = {Elsworthy, R. J. and King, M. C. and Grainger, A. and Fisher, E. and Crowe, J. A. and Alqattan, S. and Ludlam, A. and Hill, D. E. J. and others},
title = {{Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation}},
journal = {Molecular and cellular neurosciences},
year = {2021},
doi = {10.1016/j.mcn.2021.103631},
pmid = {34022327},
url = {https://doi.org/10.1016/j.mcn.2021.103631}
}
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Key findings
- Results The ratio of AβPP isoforms (130:110kDa) was significantly reduced in neuron and astrocyte co-cultures carrying PSEN1 gene mutations compared to control, and mature ADAM10 expression was lower in these cells. sAβPP-α was also significantly reduced in L286V mutation, but not in the R278I mutation cells.
- The Aβ1-42:40 ratio was significantly elevated in R278I cells.
- Antioxidant status was significantly lower in R278I cells compared to control cells.
- Conclusions This data provides evidence that the PSEN1 mutations L286V and R278I significantly alter protein expression associated with AβPP processing and cellular redox status.
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Study details
- Evidence strengthLow
How this study scored 40/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular and cellular neurosciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “ipsc”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34022327) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
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