Neuronal calcium dysregulation in mice at an early stage of tauopathy and its alleviation by a tau antibody

Abstract

AbstractBackgroundTau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. How tau antibodies restore neuronal function remains unknown. Neuronal activity can be monitored by two‐photon calcium imaging in awake and behaving animals. Using this method, we observed altered neuronal calcium activity in the motor cortex of 12‐month‐old JNPL3 tauopathy mice during quiet wakefulness or forced running (Wu Q et al, Neurobiol. Dis. 2021). We also demonstrated that a mouse monoclonal antibody, targeting phosphorylated tau‐Ser396/Ser404, significantly restored the abnormal calcium activity and decreased pathological tau levels in these mice. Analysis of possible neuronal functional deficits and tau antibody efficacy in younger tauopathy mice warrants further investigation.MethodsSomatic calcium activity in the motor cortex of 6‐month‐old JNPL3 mice were assessed by two‐photon microscopy when animals were either resting or running on a treadmill. At this age, JNPL3 mice are in their early stage of tauopathy. The frequency, amplitude and total activity of calcium transients were analyzed and compared between wild‐type and JNPL3 mice. After the first imaging session, two doses (100 µg each) of a tau antibody were administered intravenously to JNPL3 mice four days apart. The somatic calcium activity was assessed again in these animals four days later, and compared to their neuronal calcium activity profile before tau antibody treatment.ResultsWe found abnormal cortical calcium activity in resting and running JNPL3 mice at 6 months of age. Brain levels of pathological tau correlated with the degree of calcium dysfunction. Acute treatment with a tau antibody attenuated these changes, whereas littermate JNPL3 mice treated with control IgG showed no improvements.ConclusionThese findings revealed neuronal calcium dysregulation in JNPL3 mice at an early stage of tauopathy that was partially corrected by an acute tau antibody treatment, analogous to our prior findings at a later stage of tauopathy. Together, these results indicate that neuronal dysfunction correlates with tau pathology at various stages of tauopathy, which can be consistently alleviated by a tau antibody treatment. This type of functional evaluation in vivo is a valuable way to study tau pathogenesis, and assess therapeutic efficacy at different stages of tauopathy.