Early depletion of CA1 neurons and late neurodegeneration in a mouse tauopathy model

Alzheimer's disease (AD) and tauopathies, such as frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. Further neuropathological characteristics include synaptic loss, neurodegeneration and brain atrophy. Here, we explored the association between hyperphosphorylated tau species, brain atrophy, synaptic and neuronal loss in a mouse model (rTg4510) carrying the human tau (hTau) P301L mutation found in a familiar form of FTD. We established that hTau expression during the first 6 postnatal weeks was important for the progression of tauopathy in rTg4510 mice. Short term suppression of postnatal hTau expression delayed the onset of tau pathology by approximately 6 months in this model. Early postnatal hTau expression was detrimental to CA1 neurons of the hippocampus and reduced neuronal numbers in 6-10 weeks young rTg4510 mice prior to the appearance of hyperphosphorylated hTau species in the hippocampus. Hyperphosphorylated hTau species emerged from 10 to 24 weeks of age and were associated with increased ubiquitin levels, gliosis, and brain atrophy and preceded the synaptic loss and CA1 neurodegeneration that occurred at 48 weeks of age. We present two consequences of hTau expression in CA1 in rTg4510 mice: an early decrease in neuron number already established prior to the presence of hyperphosphorylated tau species and a later neurodegeneration dependent on hyperphosphorylated tau. Neurodegeneration and synaptic protein loss were completely prevented when hTau expression was suppressed prior to the appearance of hyperphosphorylated tau species. Suppression of hTau expression after the onset of tau hyperphosphorylation and tangle pathology initiated at 16 weeks partially rescued neuronal loss at 48 weeks of age, while a reduction of neurodegeneration was no longer possible when hTau suppression was introduced as late as at 24 weeks of age. Our results in rTg4510 mice argue that it is promising to lower hyperphosphorylated tau species at early stages of tau pathology to protect from neurodegeneration.