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Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease
Akshay Kapadia, Fabian Schuhmann, Ezgi Daşkın, Jochen Walter, Isabell Lindahl, Neda Rahmani, Tjado H. J. Morrema, Annemieke J.M. Rozemüller et al.. The EMBO Journal, 2026-09-01
Topic: Brain proteins, microglia and lab models
The study of Alzheimer's disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of endogenous APP metabolite levels suggests a role for APP-CTFs, in particular APP-CTFβ, in regulating glutamatergic synaptic transmission. Presynaptic accumulation of APP-CTFβ promotes its oligomerization, increases synaptic vesicle docking, and causes vesicle release defects, accompanied by enhanced neuronal network activity. Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons. Strikingly, acute application of Aβ preparations enriched in monomeric species counteracts APP-CTFβ-induced hyperexcitability. Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer's disease.
Key findings
- Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses.
- Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons.
- Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer's disease.
Why it matters
This laboratory and post-mortem brain study found that a fragment of amyloid precursor protein, APP-CTFβ, accumulates at excitatory synapses and may contribute to early synaptic alterations in Alzheimer's disease. It identifies a possible mechanism, not a treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 38/100
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 | 5 / 5 | 2026 — within 1 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Anne‐Sophie Hafner: h-index 12 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 10 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42681024) |
| Free to read | 2 / 2 | Free to read |
| Total | 38 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s44318-026-00899-6
- PubMed: 42681024
- Original source →
- Free full text: The EMBO Journal →
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
Kapadia, A., Schuhmann, F., Daşkın, E., Walter, J., Lindahl, I., Rahmani, N., et al. (2026). Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease. The EMBO Journal. https://doi.org/10.1038/s44318-026-00899-6
Vancouver
Kapadia A, Schuhmann F, Daşkın E, Walter J, Lindahl I, Rahmani N, et al. Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease. The EMBO Journal. 2026. doi:10.1038/s44318-026-00899-6. PMID: 42681024.
BibTeX
@article{kapadia2026-42681024,
author = {Kapadia, Akshay and Schuhmann, Fabian and Daşkın, Ezgi and Walter, Jochen and Lindahl, Isabell and Rahmani, Neda and Morrema, Tjado H. J. and Rozemüller, Annemieke J.M. and others},
title = {{Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease}},
journal = {The EMBO Journal},
year = {2026},
doi = {10.1038/s44318-026-00899-6},
pmid = {42681024},
url = {https://doi.org/10.1038/s44318-026-00899-6}
}
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Referenced by this study and also in the alzhub library, so you can read them here.
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