The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice

Kuhnau, L.; Jimenez, G. A.; Hack, W.; Varada, S.; Gladen Kolarsky, N.; Kim, S.; Klein, F.; Banerji, T.; Quinn, J. F.; Scanlan, T. S.; Gray, N. E.

doi:10.64898/2026.07.31.741838

bioRxiv · 10.64898/2026.07.31.741838

The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice

Kuhnau, L.·Jimenez, G. A.·Hack, W.·Varada, S.·Gladen Kolarsky, N.·Kim, S.·Klein, F.·Banerji, T.·Quinn, J. F.·Scanlan, T. S.·Gray, N. E.

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Abstract

BackgroundInflammation is an early event that substantially influences Alzheimers 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. ObjectiveEvaluate the effects of Sob-AM2 on cognition, AD pathology and microglial activity in the 5xFAD mouse model of amyloid-beta (A{beta}) accumulation. MethodsSeven-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. ResultsSob-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 A{beta} 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. ConclusionThese 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.

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Kuhnau, L., Jimenez, G. A., Hack, W., Varada, S., Gladen Kolarsky, N., Kim, S., Klein, F., Banerji, T., Quinn, J. F., Scanlan, T. S., Gray, N. E.. 2026-08-05. The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice. https://doi.org/10.64898/2026.07.31.741838

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