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A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease
Ahammad RU, Spencer B, Quach B, Salehi S, Rissman RA.. Alzheimer's & dementia (New York, N. Y.), 2025-04-01
Topic: Brain proteins, microglia and lab models
Introduction Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by abnormal protein aggregation, with amyloid beta (Aβ) and α-synuclein (α-syn) as key pathological markers. Increasing evidence highlights a pathological interplay between Aβ and α-syn, exacerbating neurodegeneration in both AD and PD. In this study, we evaluated the effects of reducing amyloid precursor protein (APP) processing on α-syn pathology using a splice-switching oligonucleotide (SSO) targeting APP exon 15 in Thy1-α-syn transgenic (α-syn-tg) mice. Methods α-syn-tg mice received systemic APP SSO treatment. Immunohistochemistry and immunoblotting assessed α-syn, phosphorylated α-syn (P-Syn), and APP C-terminal fragments (CTFs) in the cortex, hippocampus, and thalamus. Neuronal integrity in different brain regions were examined, and behavioral assessments evaluated cognitive and motor functions. Results APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region. Interestingly, α-syn-tg mice exhibited elevated levels of alternative APP CTFs, which were reduced by APP SSO treatment, implicating APP processing dysregulation in α-syn pathology. Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice. Discussion Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies. While no behavioral changes were observed in transgenic mice, further research exploring different models and conditions may provide additional insights into the full range of therapeutic benefits. Future studies should optimize delivery methods and explore combination therapies to enhance outcomes in neurodegenerative diseases with overlapping proteinopathies. Highlights APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.Neuronal loss in the hippocampal CA3 region is restored following APP SSO treatment.Behavioral assessments show no significant changes in female α-syn-tg mice.Findings support APP modulation as a potential strategy for synucleinopathies.
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APA 7th
Ahammad, R. U., Spencer, B., Quach, B., Salehi, S., & Rissman, R. A. (2025). A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease. Alzheimer's & dementia (New York, N. Y.). https://doi.org/10.1002/trc2.70117
Vancouver
Ahammad RU, Spencer B, Quach B, Salehi S, Rissman RA. A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease. Alzheimer's & dementia (New York, N. Y.). 2025. doi:10.1002/trc2.70117. PMID: 40556661.
BibTeX
@article{ahammad2025-40556661,
author = {Ahammad, R. U. and Spencer, B. and Quach, B. and Salehi, S. and Rissman, R. A.},
title = {{A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease}},
journal = {Alzheimer's \& dementia (New York, N. Y.)},
year = {2025},
doi = {10.1002/trc2.70117},
pmid = {40556661},
url = {https://doi.org/10.1002/trc2.70117}
}
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Key findings
- Results APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region.
- Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice.
- Discussion Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies.
- Highlights APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.Neuronal loss in the hippocampal CA3 region is restored following APP SSO treatment.Behavioral assessments show no significant changes in female α-syn-tg mice.Findings support APP modulation as a potential strategy for synucleinopathies.
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Study details
- Evidence strengthLow
How this study scored 48/100
Published in a leading specialty journal. Scored zero for study design, sample size, 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 28 of the 58 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia (New York, N. Y.)) |
| 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 | 4 / 5 | 2025 — within 3 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 | Laboratory or animal study (title names “mouse”) — scores zero |
| 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 40556661) |
| Free to read | 2 / 2 | Free to read |
| Points | 28 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 28 of the 58 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
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