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Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction
Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M et al.. Annals of neurology, 2011-06-01
Topic: Brain proteins, microglia and lab models
Objective The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations. Results We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.
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APA 7th
Hata, S., Fujishige, S., Araki, Y., Taniguchi, M., Urakami, K., Peskind, E., et al. (2011). Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction. Annals of neurology. https://doi.org/10.1002/ana.22343
Vancouver
Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, et al. Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction. Annals of neurology. 2011. doi:10.1002/ana.22343. PMID: 21681798.
BibTeX
@article{hata2011-21681798,
author = {Hata, S. and Fujishige, S. and Araki, Y. and Taniguchi, M. and Urakami, K. and Peskind, E. and Akatsu, H. and Araseki, M. and others},
title = {{Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction}},
journal = {Annals of neurology},
year = {2011},
doi = {10.1002/ana.22343},
pmid = {21681798},
url = {https://doi.org/10.1002/ana.22343}
}
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Key findings
- Results We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants.
- Interpretation These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.
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Study details
- Participants158
- Evidence strengthModerate
How this study scored 52/100
Published in a leading specialty journal. Scored zero for study design, 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 30 of the 58 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| 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 | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2011 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 158 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 21681798) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 30 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 30 of the 58 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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