TREM2 is a membrane receptor expressed on microglia that plays a pivotal role in the organization and function of these innate immune cell components within the neurodegenerated brain. Whereas TREM2 deletion has been studied extensively in experimental beta-amyloid and Tau-based models of Alzheimer’s disease, its engagement, and subsequent agonism have not been tested in the context of Tau pathology. Herein, we explored the effects of Ab-T1, an agonistic TREM2 monoclonal antibody on Tau uptake, phosphorylation, seeding, and spreading as well as its therapeutic efficacy in a Tauopathy model. Ab-T1 enhanced the uptake of misfolded Tau to microglia and induced a non-cell autonomous attenuation of spontaneous Tau seeding and phosphorylation in primary neurons from human Tau transgenic mice. Ex vivo, incubation with Ab-T1 led to a significant reduction in the seeding of Tau pathology in the hTau murine organoid brain system. Systemic administration of Ab-T1 resulted in reduced Tau pathology and propagation when hTau was stereotactically injected into the hemispheres of hTau mice. Intraperitoneal treatment with Ab-T1 lead to attenuation of cognitive decline in the hTau mice that was associated with reduced neurodegeneration and synaptic preservation with amelioration of the global neuroinflammatory program. Collectively, these observations show that TREM2 engagement with an agonistic antibody result in reduced Tau burden concomitant with attenuated neurodegeneration ascribed to the education of resident microglia. These results may suggest that despite the opposing results with regard to the effect of TREM2 knockout in experimental Tau-based model systems, receptor engagement and activation by Ab-T1 appears to possess beneficial effects with respect to the various mechanisms mediating Tau-driven neurodegeneration.

Background: Transthyretin cardiac amyloidosis (ATTR-CA) results from the extracellular deposition of misfolded transthyretin (mis-TTR) and promotes progressive cardiac dysfunction. Current therapies, such as stabilizers and silencers, reduce further fibril accumulation but fail to clear existing deposits. Monoclonal antibodies (mAbs) targeting mis-TTR have emerged as promising disease-modifying agents, supported by recent observations of circulating anti-TTR antibodies in patients who exhibited spontaneous clinical improvement. Methods: This study aimed to purify natural anti-TTR antibodies from two ATTR-CA patients and compare the respective binding properties to those of a previously described therapeutic anti-TTR mAb fragment (Ab-A F(ab')2). Statistical significance was determined using Student's t-test. Results: Both natural antibodies and the Ab-A F(ab')2 demonstrated high-affinity binding to misfolded TTR (n = 3), while the competition assays revealed dose-dependent inhibition, indicating shared epitope recognition. Conclusions: These findings provide translational evidence that therapeutic anti-TTR mAbs may mimic naturally protective antibodies, suggesting that these antibodies could promote amyloid clearance and deliver true disease-modifying benefits in ATTR-CA.