The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures
Lannette-Weimann N, Huyvaert M, Limoge F, Lemaire M, Gao V, Maurier F, Guyot K, Henocq C et al.. bioRxiv, 2026-10-30
Topic: Disease mechanisms in lab and animal studies
The rs28834970 regulatory variant was identified as the most functionally relevant in our model, with the C risk allele promoting transcription factor C/EBPβ binding within a cis-regulatory element. In hNCs, the homozygous rs28834970 CC genotype reduced total PYK2 levels by more than 80%, while increasing the proportion of phosphorylated (activated) PYK2. Transcriptomic analysis revealed 724 downregulated and 113 upregulated gene sets, with altered expression of genes involved in extracellular matrix organization, cytoplasmic translation and neurotransmitter secretion. MEA recordings showed reduced network recruitment and altered burst organization. Immunocytochemistry in microfluidic devices consistently revealed that rs28834970 impacts dendritic development and postsynaptic maturation. The risk genotype significantly elevated Tau phosphorylation at pathological sites (Thr181, Thr217, Thr231, Ser202-Thr205, Ser396-Ser404), and enhanced APP processing, resulting in decreased levels of APP and CTF but increased levels of sAPPα, sAPPβ and Aβ. The rs28834970 C risk allele mechanistically links AD susceptibility to downregulation of PTK2B/PYK2 expression and to the increase in Tau pathology and Aβ levels while compromising synaptic structure and function.
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APA 7th
Lannette-Weimann, N., Huyvaert, M., Limoge, F., Lemaire, M., Gao, V., Maurier, F., et al. (2026). The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures. bioRxiv. https://doi.org/10.64898/2026.10.26.761842
Vancouver
Lannette-Weimann N, Huyvaert M, Limoge F, Lemaire M, Gao V, Maurier F, et al. The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures. bioRxiv. 2026. doi:10.64898/2026.10.26.761842.
BibTeX
@article{lannetteweimann2026-70beeb19,
author = {Lannette-Weimann, N. and Huyvaert, M. and Limoge, F. and Lemaire, M. and Gao, V. and Maurier, F. and Guyot, K. and Henocq, C. and others},
title = {{The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.26.761842},
url = {https://doi.org/10.64898/2026.10.26.761842}
}
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Key findings
- The rs28834970 regulatory variant was identified as the most functionally relevant in our model, with the C risk allele promoting transcription factor C/EBPβ binding within a cis-regulatory element.
- In hNCs, the homozygous rs28834970 CC genotype reduced total PYK2 levels by more than 80%, while increasing the proportion of phosphorylated (activated) PYK2.
- Transcriptomic analysis revealed 724 downregulated and 113 upregulated gene sets, with altered expression of genes involved in extracellular matrix organization, cytoplasmic translation and neurotransmitter secretion.
- MEA recordings showed reduced network recruitment and altered burst organization.
- Immunocytochemistry in microfluidic devices consistently revealed that rs28834970 impacts dendritic development and postsynaptic maturation.
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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 randomized / 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 multicenter 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) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter 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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