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.

Introduction. Alpha synuclein (αSyn) misfolding plays a requisite role in the pathogenesis of synucleinopathies. Direct toxicity to neurons, triggering neuroinflammation as well as the spreading and seeding of αSyn pathology are essential pathogenetic underlying mechanisms. Immunotherapy in experimental Parkinson’s disease (PD) has been shown to be consistently effective in preclinical models, yet the initial clinical trials with monoclonal antibodies (mAbs) yielded marginal results if any. Aiming to overcome some of the limitation of this approach, we aimed to select an αSyn binding scFv antibody format and test it in multiple experimental PD in vivo models. Methods. We cloned the lead αSyn scFv based on preselection of human phage display libraries of human Fab. The selected of scFv targeting both oligomers and pre-formed fibrils (PFF) of αSyn were tested for their ability to protect neurons from triggered toxicity, influence their uptake to microglia, and accelerate misfolded αSyn degradation. The lead scFv- sMB08, was also tested for its ability to impact αSyn aggregation as well as spreading and seeding. Results. sMB08 was shown to protect neurons from misfolded αSyn mediated toxicity, promote its intracellular degradation, and to reduce its uptake by microglia. sMB08 exhibited anti-inflammatory properties, including its ability to attenuate adaptive αSyn autoimmunity and ameliorate proinflammatory cytokine expression in brains of mice stereotactically injected with PFF. Employing three experimental models of PD, intranasal treatment with sMB08 attenuated motoric dysfunction and achieved acceptable brain levels by pharmacokinetic analysis, leading to significant preservation of dopaminergic n neurons. Conclusion: sMB08, a scFv targeting both αSyn oligomers and PFF, due to its small size facilitating paraneural brain penetration and avoidance of nonspecific inflammation, appears as an attractive approach to test in patients with PD by addressing the major mechanisms that mediate misfolded αSyn driven pathology.

ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia.