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Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation
Koch P, Tamboli IY, Mertens J, Wunderlich P, Ladewig J, Stüber K, Esselmann H, Wiltfang J et al.. The American journal of pathology, 2012-04-14
Topic: Disease mechanisms in lab and animal studies
Alzheimer's disease (AD) is the most frequent cause of dementia. There is compelling evidence that the proteolytic processing of the amyloid precursor protein (APP) and accumulation of amyloid-β (Aβ) peptides play critical roles in AD pathogenesis. Due to limited access to human neural tissue, pathogenetic studies have, so far, mostly focused on the heterologous overexpression of mutant human APP in non-human cells. In this study, we show that key steps in proteolytic APP processing are recapitulated in neurons generated from human embryonic and induced pluripotent stem cell-derived neural stem cells (NSC). These human NSC-derived neurons express the neuron-specific APP(695) splice variant, BACE1, and all members of the γ-secretase complex. The human NSC-derived neurons also exhibit a differentiation-dependent increase in Aβ secretion and respond to the pharmacotherapeutic modulation by anti-amyloidogenic compounds, such as γ-secretase inhibitors and nonsteroidal anti-inflammatory drugs. Being highly amenable to genetic modification, human NSCs enable the study of mechanisms caused by disease-associated mutations in human neurons. Interestingly, the AD-associated PS1(L166P) variant revealed a partial loss of γ-secretase function, resulting in the decreased production of endogenous Aβ40 and an increased Aβ42/40 ratio. The PS1(L166P) mutant is also resistant to γ-secretase modulation by nonsteroidal anti-inflammatory drugs. Pluripotent stem cell-derived neurons thus provide experimental access to key steps in AD pathogenesis and can be used to screen pharmaceutical compounds directly in a human neuronal system.
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APA 7th
Koch, P., Tamboli, I. Y., Mertens, J., Wunderlich, P., Ladewig, J., Stüber, K., et al. (2012). Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. The American journal of pathology. https://doi.org/10.1016/j.ajpath.2012.02.012
Vancouver
Koch P, Tamboli IY, Mertens J, Wunderlich P, Ladewig J, Stüber K, et al. Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. The American journal of pathology. 2012. doi:10.1016/j.ajpath.2012.02.012. PMID: 22510327.
BibTeX
@article{koch2012-22510327,
author = {Koch, P. and Tamboli, I. Y. and Mertens, J. and Wunderlich, P. and Ladewig, J. and Stüber, K. and Esselmann, H. and Wiltfang, J. and others},
title = {{Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation}},
journal = {The American journal of pathology},
year = {2012},
doi = {10.1016/j.ajpath.2012.02.012},
pmid = {22510327},
url = {https://doi.org/10.1016/j.ajpath.2012.02.012}
}
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Key findings
- Interestingly, the AD-associated PS1(L166P) variant revealed a partial loss of γ-secretase function, resulting in the decreased production of endogenous Aβ40 and an increased Aβ42/40 ratio.
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Study details
- Evidence strengthLow
How this study scored 36/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / 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 multicenter collaboration, so those were left out: it earned 21 of the 58 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The American journal of pathology) |
| 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 | 1 / 5 | 2012 — within 20 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22510327) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 21 of the 58 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | — |
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