Efficacy of the murine version of E2814 in a validated AD brain seed‐injection model in hTau mice

Abstract

AbstractBackgroundAs Alzheimer’s disease progresses, pathological tau spreads through the brain via synaptically connected pathways. Tau proteins containing the microtubule binding region (MTBR) may be essential to form extracellular ‘seeds’ that initiate and propagate pathology. To simulate this process preclinically, we have further characterised an AD brain‐derived seed‐injection in vivo model using hTau mice that overexpress all six isoforms of human wild‐type tau (Andorfer et al., 2003). In further follow up studies, mice were treated with the 7G6‐IgG2a antibody, which is the murine counterpart of E2814, an anti‐tau antibody currently in clinical trials that recognises the MTBR (Roberts et al., 2020).MethodIn a validation study, insoluble fraction or whole homogenate from human AD brain (‘seed’) was directly injected into the left hippocampus of 6‐month‐old hTau mice or their tau null littermates. At different times after seed injection, the generation of insoluble tau was quantified in selected brain regions (hippocampus and cortex) by western blotting following tissue fractionation with detergents.In a subsequent therapeutic intervention study, animals were treated peripherally with a control mouse IgG2a antibody or 7G6‐IgG2a at different doses (3, 10, and 40 mg/kg). Levels of insoluble tau in the hippocampus and cortex were quantified as described above. Terminal CSF was also collected to measure target engagement of antibody. Additionally, immunohistochemistry using the AT8 antibody that detects pathological forms of phospho‐tau proteins was performed on brains from a limited number of animals receiving the highest dose of control IgG2a or 7G6‐IgG2a.ResultAD brain insoluble fraction was superior to homogenate when used as a seed in the hTau mouse.Peripheral treatment of seeded hTau mice with the 7G6‐IgG2a antibody (40 mg/kg) resulted in a significant reduction of insoluble tau in multiple brain regions. Antibody target engagement also increased in the CSF from treated animals in a dose‐dependent manner.ConclusionAD seed‐injection in hTau mice has been further validated and can be used in therapeutic intervention studies. The murine version of E2814, 7G6‐IgG2a, reduced pathological tau seeding and spreading in this model. The nonclinical data obtained here further supports E2814 being tested in clinical trials.