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HnRNPAB -targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimer’s disease-associated alternative splicing
Jiang T, Xu X, Yu Y, Zhu C, Ma C, Tang Y, Min L, Tan M et al.. bioRxiv, 2026-07-03
Topic: Genetics and APOE
Aberrant alternative splicing alters multiple disease-associated splicing events, including MAPT exon 10 inclusion linked to tau pathology, and thereby impacts Alzheimer’s disease (AD) progression. Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) functions as a splicing regulator, yet its roles in AD remain poorly defined. Here, we identified AB332, the full-length isoform of hnRNPAB, as a novel repressor of MAPT exon 10 inclusion. AB332 binds a conserved AAUAU motif and recruits RBMX and RBMXL1 through its RRM and glycine-rich domains to assemble a complex. Beyond MAPT , AB332 modulates a network of splicing events in multiple AD-associated genes, including STAG2, ApoER2, MCL-1, PICALM , and zDHHC7 . Importantly, the exon 7-skipping isoform AB285 lacks these activities. Transcriptomic analysis of post-mortem brain tissues from AD patients revealed reduced expression of hnRNPAB , while selective downregulation of AB332 was confirmed in the hippocampus of 3xTg AD mice. We performed a systematic antisense oligonucleotide-tiling screen targeting hnRNPAB exon 7 and its flanking intronic regions, identifying ASO30 that specifically upregulated AB332 expression. In 3xTg AD mice, ASO30 restored hippocampal AB332 levels, reduced pathological tau phosphorylation, and rescued cognitive deficits. These findings define a molecular mechanism by which AB332 regulates AD-associated splicing events, thereby providing a therapeutic strategy targeting hnRNPAB for AD. GRAPHICAL ABSTRACT
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APA 7th
Jiang, T., Xu, X., Yu, Y., Zhu, C., Ma, C., Tang, Y., et al. (2026). HnRNPAB -targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimer’s disease-associated alternative splicing. bioRxiv. https://doi.org/10.64898/2026.07.02.736008
Vancouver
Jiang T, Xu X, Yu Y, Zhu C, Ma C, Tang Y, et al. HnRNPAB -targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimer’s disease-associated alternative splicing. bioRxiv. 2026. doi:10.64898/2026.07.02.736008.
BibTeX
@article{jiang2026-5ac0488b,
author = {Jiang, T. and Xu, X. and Yu, Y. and Zhu, C. and Ma, C. and Tang, Y. and Min, L. and Tan, M. and others},
title = {{HnRNPAB -targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimer’s disease-associated alternative splicing}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.07.02.736008},
url = {https://doi.org/10.64898/2026.07.02.736008}
}
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Key findings
- Transcriptomic analysis of post-mortem brain tissues from AD patients revealed reduced expression of hnRNPAB , while selective downregulation of AB332 was confirmed in the hippocampus of 3xTg AD mice.
- These findings define a molecular mechanism by which AB332 regulates AD-associated splicing events, thereby providing a therapeutic strategy targeting hnRNPAB for AD.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. 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 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 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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