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Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity
Altan Rentsendorj, Jean-Philippe Vit, Alexandre Hutton, Yosef Koronyo, Saba Shahin, Edward Robinson, Ernesto Barron, Anthony Rodriguez et al.. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026-08-29
Topic: Disease mechanisms in lab and animal studies
Synaptic dysfunction is a major driver of cognitive decline in Alzheimer's disease (AD), yet its extent and molecular basis in the retina remain poorly defined. We integrated postmortem retinal and matched brain histopathology with ultrastructural, proteomic, biochemical, and machine-learning analyses across cognitively normal, mild cognitive impairment, and AD cohorts. Retinal glutamatergic synapses exhibited early, progressive degeneration, marked by loss of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), along with ribbon synapse ultrastructural disruption. Synaptic deficits correlated with amyloid-β42 (Aβ42), pathogenic tau, oxidative stress, the Aβ-binding p75 neurotrophin receptor, and glial activation that paralleled disease progression. Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways. The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation. Mechanistically, fibrillar Aβ42 induced rapid UCHL1 and synaptic depletion in human and murine neurons before overt neurodegeneration. Machine-learning models identified retinal UCHL1 as the strongest predictor of Braak stage and cognitive impairment. These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.
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APA 7th
Rentsendorj, A., Vit, J.-P., Hutton, A., Koronyo, Y., Shahin, S., Robinson, E., et al. (2026). Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity. Advanced science (Weinheim, Baden-Wurttemberg, Germany). https://doi.org/10.1002/advs.202600020
Vancouver
Rentsendorj A, Vit J.-P, Hutton A, Koronyo Y, Shahin S, Robinson E, et al. Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026. doi:10.1002/advs.202600020. PMID: 42666080.
BibTeX
@article{rentsendorj2026-42666080,
author = {Rentsendorj, Altan and Vit, Jean-Philippe and Hutton, Alexandre and Koronyo, Yosef and Shahin, Saba and Robinson, Edward and Barron, Ernesto and Rodriguez, Anthony and others},
title = {{Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
doi = {10.1002/advs.202600020},
pmid = {42666080},
url = {https://doi.org/10.1002/advs.202600020}
}
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.
Key findings
- Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways.
- The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation.
- These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.
Study details
- Evidence strengthLow
How this study scored 45/100
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. 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, multi-centre collaboration and free to read, so those were left out: it earned 25 of the 56 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Advanced science (Weinheim, Baden-Wurttemberg, Germany)) |
| 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 | 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 | — / 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 42666080) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 25 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 25 of the 56 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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