[p3–178]: in vivo two-photon imaging of the effects of tauopathy and amyloidopathy on synapses

A progressive loss of synapses occurs at the early clinical stages of Alzheimer's Disease and has been correlated with cognitive deficits in patients. However, it is relatively unknown how synapse dynamics are affected by the two main pathological hallmarks of AD; the accumulation of tau and beta-amyloid. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of human tauopathy (rTg4510) and amyloidopathy (J20). Following a craniotomy, adeno-associated virus expressing green fluorescent protein was injected into the somatosensory cortex to enable the visualisation of neurons and a cranial window was implanted for long-term imaging. GFP-labelled neurons were imaged in both models during a time period which spanned the onset of pathology. The gross morphology of neurites and the dynamics of their synaptic structures were assessed as the pathology progressed. In rTg4510s, gross morphological changes such as the presence of dystrophic neurites were visible as the tauopathy progressed and these were found to have a distinctive morphological phenotype prior to neurite degeneration. Alongside this, synapse instability and loss were also observed and could be prevented by suppressing the P301L transgene. In J20 animals, amyloid plaques increased in size and density over time and spine density was affected by the dendrite's proximity to plaques. Both tauopathy and amyloidopathy have effects on synapses as the respective pathology progressed. These results will inform subsequent drug discovery studies to identify novel therapies to stabilize synapse loss in AD. In rTg4510s, gross morphological changes such as the presence of dystrophic neurites were visible as the tauopathy progressed and these were found to have a distinctive morphological phenotype prior to neurite degeneration. Alongside this, synapse instability and loss were also observed and could be prevented by suppressing the P301L transgene. In J20 animals, amyloid plaques increased in size and density over time and spine density was affected by the dendrite's proximity to plaques.