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Integrative Multiomics Analysis Reveals a Coordinated Molecular Signature of Neuroresilience in human MAPT-knockout hiPSC-derived Neurons with relevance for Alzheimer’s and Neurodegenerative Disease
Jajin EA, Zempel H.. Research Square, 2026-10-14
Topic: Disease mechanisms in lab and animal studies
Background Transcriptome data provides a robust analytical viewpoint about cellular processes in Alzheimer’s Disease (AD). Integrative multiomics analysis including transcriptome and proteome data elucidates the underlying mechanisms of this progressive disease. The microtubule-associated protein Tau ( MAPT ) is central to Alzheimer’s disease (AD) pathogenesis. We demonstrated that Tau loss confers resistance to amyloid-beta (Aβ) toxicity in AD-relevant human glutamatergic neurons, but the active molecular reprogramming driving this neuroresilience remains poorly defined. Methods We employed an integrative multiomics approach, combining temporal transcriptomics (3h and 24h post-Aβ exposure) with newly processed proteomic layers from terminally differentiated and electrophysiologically active human iPSC-derived neurons (WT vs. MAPT -Knockout (KO)). Analysis included DESeq2, WGCNA, and GSEA, followed by cross-layer integration to identify convergent molecular signatures and master regulators. Results Our analysis revealed a striking transcriptomic stagnation in WT neurons, which failed to mount an adaptive response to Aβ stress. In contrast, MAPT -KO neurons exhibited a pre-established resilience signature characterized by profound baseline reprogramming. WGCNA identified a co-expression gene cluster (turquoise module, r = 0.74) strongly associated with the MAPT -KO phenotype and enriched in mitochondrial transport, autophagy, and synaptic homeostasis. Key hub genes including SIM1, INPP5F, and AKR1C2 established a mitochondrial metabolic defense mechanism. Multiomics integration identified 27 core consensus hits (e.g., COL17A1, PER3, ST3GAL6) consistently preserved across both layers. Furthermore, transcription factor enrichment identified KLF4 (Kruppel-like Factor 4), a key regulator of neuronal differentiation and metabolic adaptation, as the master regulator orchestrating this protective network. Conclusion These findings demonstrate that Tau deletion induces an active, multilevel gain-of-resilience rather than passive resistance. By identifying a KLF4-driven molecular signature, this study highlights novel therapeutic targets that could be leveraged to induce synthetic resilience in AD patients, protecting neurons from amyloid-induced bioenergetic and structural collapse.
Key findings
- We demonstrated that Tau loss confers resistance to amyloid-beta (Aβ) toxicity in AD-relevant human glutamatergic neurons, but the active molecular reprogramming driving this neuroresilience remains poorly defined.
- Results Our analysis revealed a striking transcriptomic stagnation in WT neurons, which failed to mount an adaptive response to Aβ stress.
- WGCNA identified a co-expression gene cluster (turquoise module, r = 0.74) strongly associated with the MAPT -KO phenotype and enriched in mitochondrial transport, autophagy, and synaptic homeostasis.
- Conclusion These findings demonstrate that Tau deletion induces an active, multilevel gain-of-resilience rather than passive resistance.
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 (Research Square) |
| 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. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Jajin, E. A., & Zempel, H. (2026). Integrative Multiomics Analysis Reveals a Coordinated Molecular Signature of Neuroresilience in human MAPT-knockout hiPSC-derived Neurons with relevance for Alzheimer’s and Neurodegenerative Disease. Research Square. https://doi.org/10.21203/rs.3.rs-11112521/v1
Vancouver
Jajin EA, Zempel H. Integrative Multiomics Analysis Reveals a Coordinated Molecular Signature of Neuroresilience in human MAPT-knockout hiPSC-derived Neurons with relevance for Alzheimer’s and Neurodegenerative Disease. Research Square. 2026. doi:10.21203/rs.3.rs-11112521/v1.
BibTeX
@article{jajin2026-f5a97635,
author = {Jajin, E. A. and Zempel, H.},
title = {{Integrative Multiomics Analysis Reveals a Coordinated Molecular Signature of Neuroresilience in human MAPT-knockout hiPSC-derived Neurons with relevance for Alzheimer’s and Neurodegenerative Disease}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11112521/v1},
url = {https://doi.org/10.21203/rs.3.rs-11112521/v1}
}