P1–002: Synaptic degeneration and memory loss in a model of tauopathy

Alzheimer's disease (AD) is characterized by filamentous inclusions of the microtubule associated protein tau, known as neurofibrillary tangles (NFTs) and by beta–amyloid deposits. A direct link between these pathological hallmarks and behavioral manifestations of the disease has not been established. The memory impairment in AD correlates better with the progression of tau pathology than that of amyloid pathology, however, the strongest correlate to memory impairment is loss of synapses and synaptic function. We are currently examining the connection between tau dependent cognitive dysfunction and synaptic disruption by taking advantage of a unique mouse model of conditional tau pathology, known as rTg4510. This mouse line contains the P301L tau mutation and a tet–off activator transgene that allows for suppression of mutant tau expression via doxycycline. 1) Determine if disruptions in synapses are involved in the pathologic and memory defects that have been observed in this mouse model. 2) Determine if suppressing mutant tau expression with doxycycline treatment leads to a recovery of memory that is related to repair of pathologic changes in synapses. We have examined mice at multiple ages using the Morris Water Maze to test memory deficits. Synaptic degeneration is being analyzed based on changes in pre– and postsynaptic markers and loss of dendritic spines. rTg4510 mice develop NFTs, neuronal death and memory loss that is reversible following suppression of the mutant tau transgene. Memory loss occurs before neuronal loss and recovery of memory occurs despite significant neuronal death. Thus there is a dissociation of neuronal death from the primary mechanism of memory loss in this model. Pre–synaptic synaptophysin immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell loss is observed but where spatial reference memory displays variable deficits. The memory deficits in the rTg4510 mice appear to result from changes in neuronal function rather than overall neuronal death. Initial results suggest that synaptic degeneration pre–dates neuronal loss by several months. We therefore hypothesize that memory deficits in rTg4510 mice may be due at least in part to a synaptic disorder that is reversible upon suppression of mutant tau.