Presenter of 1 Presentation
CGX101, A TREM2 AGONISTIC MONOCLONAL ANTIBODY, ATTENUATES PHOPHO-TAU BURDEN AND NEURODEGENERATION IN EXPERIMENTAL TAUOPATHY
Abstract
Aims
TREM2 is a microglial receptor that plays an important role in shaping the response of the innate immune system to misfolded proteins. However, in the pathogenesis of Alzheimer's disease, Tau appears to play at least an equally important role. Data on the influence of TREM2 on Tau pathology is inconsistent. We have thus explored the effects of our agonistic anti-TREM2 mAb, CGX101 on Tau pathology in vitro, ex vivo and in vivo in different systems modeling phopho-Tau pathology.
Methods
Neuroinflammation (RT-PCR, protein-ARRAY), synaptic markers (synaptophysin), neurodegeneration (NeuN, Cresyl-violet, caspase3), neurofibrillary tangles and cognitive function (morris water maze) were assessed in mice treated with CGX101. Tau spreading and seeding (ex-vivo, tau transgenic primary neurons) and phospho-Tau mediated toxicity were tested in vitro and ex vivo in multiple protein and immunofluorescence assays.
Results
CGX101 was shown to protect neurons from phopho-Tau mediated toxicity and conditioned medium from antibody treated microglia attenuated spreading and seeding of tau pathology in vitro in Tau transgenic primary neurons. These effects of spreading and seeding were also evident in an organoid system comprising slides of brains from mice with a dual human Tau mutation. In vivo, CGX101 treated wild type mice intracerebrally inoculated with pTau, exhibited inhibition of propagation and spreading of phospho-Tau pathology to the contralateral hemisphere. Finally, in vivo treatment with CGX101 ameliorated cognitive decline, aggregated phospho-Tau burden and neurodegeneration while facilitating synaptic preservation in hTau transgenic mice.
Conclusions
CGX101 is the first TREM2 agonist to exhibit a robust beneficial effect on neurodegeneration and Tau load in experimental tauopathy, via microglial priming.