Home › Research › Brain scans and imaging
Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, Xu Y, Chan RB et al.. The EMBO journal, 2017-10-10
Topic: Brain proteins, microglia and lab models
In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.
Key findings
- In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques.
- In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase.
Why it matters
In cell models, increased unprocessed C99 in mitochondria-associated membranes altered lipid composition and mitochondrial function, which the authors suggest may contribute to the energy defects seen in Alzheimer's. This is laboratory cell work, not a study in people, and does not test any treatment or show that targeting this process helps patients.
New to this subject? Start with our plain-English guide: Brain scans & tests →
Study details
- Evidence strengthLow
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The EMBO journal) |
| Journal's citation record | 4 / 4 | The EMBO Journal: journal h-index 563 (OpenAlex, 2026-10-29) |
| 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 | 2 / 5 | 2017 — within 10 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 234 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 21.3 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 4 / 6 | Cited 11.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 3 / 4 | Cited 66 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Estela Área-Gómez: h-index 39 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 29018038) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Pera, M., Larrea, D., Guardia-Laguarta, C., Montesinos, J., Velasco, K. R., Agrawal, R. R., et al. (2017). Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. The EMBO journal. https://doi.org/10.15252/embj.201796797
Vancouver
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, et al. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. The EMBO journal. 2017. doi:10.15252/embj.201796797. PMID: 29018038.
BibTeX
@article{pera2017-29018038,
author = {Pera, M. and Larrea, D. and Guardia-Laguarta, C. and Montesinos, J. and Velasco, K. R. and Agrawal, R. R. and Xu, Y. and Chan, R. B. and others},
title = {{Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease}},
journal = {The EMBO journal},
year = {2017},
doi = {10.15252/embj.201796797},
pmid = {29018038},
url = {https://doi.org/10.15252/embj.201796797}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
1 study in the alzhub library lists this one in its references.
Related studies in Brain scans and imaging
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.