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The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice
Kuhnau L, Jimenez GA, Hack W, Varada S, Gladen-Kolarsky N, Kim S, Klein F, Banerji T et al.. bioRxiv, 2026-08-05
Topic: Inflammation, microglia and astrocytes
Background Inflammation is an early event that substantially influences Alzheimer’s disease (AD) pathogenesis, making it a compelling target for therapeutic intervention. Sob-AM2 is a brain-penetrating thyromimetic drug capable of inducing the expression of microglial cell surface receptor TREM2, which mediates the switch from pro-inflammatory to a more restorative microglial state. Objective Evaluate the effects of Sob-AM2 on cognition, AD pathology and microglial activity in the 5xFAD mouse model of amyloid-beta (Aβ) accumulation. Methods Seven-month-old 5xFAD mice and their wild-type littermates were administered Sob-AM2 subcutaneously three times per week for 12 weeks. In the last two weeks of treatment mice underwent behavioral tests to assess cognition and monitor for off-target mobility effects. At the end of treatment, brain tissue was harvested for gene and protein expression analyses. Results Sob-AM2 treatment increased TREM2 expression in the brains of 5xFAD mice. This was accompanied by an improvement in both spatial and associative memory as well as an increase in the expression of synaptic genes synaptophysin and PSD-95. No significant changes were detected in Aβ plaque burden or the expression of microglial activation marker Iba1 in Sob-AM2 treated animals, however, the expression of the phagocytic marker CD68 was significantly increased in the hippocampus, but not the cortex, in Sob-AM2 treated 5xFAD mice. Conclusion These results suggest that the cognitive-enhancing effects of Sob-AM2 are not the result of reduced overall plaque burden. Future work is needed to further investigate the neuroprotective mechanism of Sob-AM2 and how it may be affecting microglial phenotypes.
Key findings
- Results Sob-AM2 treatment increased TREM2 expression in the brains of 5xFAD mice.
- No significant changes were detected in Aβ plaque burden or the expression of microglial activation marker Iba1 in Sob-AM2 treated animals, however, the expression of the phagocytic marker CD68 was significantly increased in the hippocampus, but not the cortex, in Sob-AM2 treated 5xFAD mice.
- Conclusion These results suggest that the cognitive-enhancing effects of Sob-AM2 are not the result of reduced overall plaque burden.
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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 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 | Laboratory or animal study (title names “5xfad”) — 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 | 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
Kuhnau, L., Jimenez, G. A., Hack, W., Varada, S., Gladen-Kolarsky, N., Kim, S., et al. (2026). The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice. bioRxiv. https://doi.org/10.64898/2026.07.31.741838
Vancouver
Kuhnau L, Jimenez GA, Hack W, Varada S, Gladen-Kolarsky N, Kim S, et al. The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice. bioRxiv. 2026. doi:10.64898/2026.07.31.741838.
BibTeX
@article{kuhnau2026-4fd9d702,
author = {Kuhnau, L. and Jimenez, G. A. and Hack, W. and Varada, S. and Gladen-Kolarsky, N. and Kim, S. and Klein, F. and Banerji, T. and others},
title = {{The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.07.31.741838},
url = {https://doi.org/10.64898/2026.07.31.741838}
}