Importance of functional outcome measures when evaluating the efficacy of tau immunotherapies

Abstract

AbstractBackgroundTau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. Using in vivo two‐photon calcium imaging, we have observed altered neuronal calcium activity in behaving JNPL3 tauopathy mice at both early and advanced stage of tauopathy. We have also shown that two mouse monoclonal antibodies, targeting phosphorylated tau‐Ser396/Ser404, partially restored these neuronal deficits (Wu Q et al Neurobiol Dis 2021, Ji C et al Alzheimers Dement AAIC 2022). Recently, we reported that novel single domain antibodies (sdAbs) and their divalent derivatives conjugated to Fc fragment showed varied efficacy to reduce tau pathology in culture, and to clear tau in brain interstitial fluid by in vivo microdialysis. Whether these sdAbs restore tauopathy‐induced neuronal deficits warrants further evaluation.MethodSomatic calcium activity in the motor cortex of homozygous 6‐month‐old JNPL3 mice was imaged by two‐photon microscopy when animals were either quiet or running. Two doses (100 µg each) of a tau IgG1‐(sdAb)2 or a control IgG1 were administered intravenously four days apart after the first imaging session. Somatic calcium activity was assessed again four days later, and compared to profile before treatment. Tau pathology was then analyzed in the mouse brain lysates by immunoblotting.ResultAbnormal cortical calcium activity was observed in resting and running JNPL3 mice at 6 months of age. Acute treatment with the tau IgG1‐(sdAb)2 did not normalize the frequency, amplitude or total activity of calcium transients in motor cortical neurons. Littermate mice treated with control IgG1 showed worsening of the tauopathy‐induced calcium dysfunction in the resting condition, and no improvement in the running condition. Interestingly, tau IgG1‐(sdAb)2 treatment decreased soluble phosphorylated tau in the treated mice, although it did not improve neuronal function. Additional analyses are ongoing, including of antibody target engagement.ConclusionThese findings confirmed neuronal calcium dysregulation in young JNPL3 mice. The failure of this particular acute tau antibody treatment to restore neuronal function is in contrast to our prior findings on two other tau antibodies targeting a different epitope, although all reduced soluble phospho‐tau. Therefore, these results highlight the importance of including a functional readout during preclinical development of tau antibodies.