Mechanisms underlying the effect of N-terminal 26-230 tau fragment on synaptic dysfunction and neurodegeneration.

Alzheimer's disease is characterized by progressive impairment of brain plasticity Although senile plaques and neurofibrillary tangles in the brain are the pathological hallmarks, their presence seems not to be related to the severity of dementia. In contrast, altered synaptic communication and neuronal loss, caused by other tau or amyloid species represent a direct pathological cause for dementia. Among tau species we focus on tau fragment (26-230) or N-tau. Clevage of tau by apoptotic proteases plays a crucial role in neurodegeneration and in the development of the neurofibrillary tangles as AD progresses. We have found that N-tau adversely affects neurons. Indeed, its overexpression has marked toxic effects on neurons that can be inhibited by the NMDAR antagonist and by inhibitors of NMDAR-associated processes such as MAP kinase and calpain. We have used conditional transgenic mice for N-tau and primary neuronal cultures overexpressing N-tau for decoding the signal transduction pathway that link Ntau expression to NMDAR activity and their upstream and downstream effectors inducing plasticity failure. Data regarding the electrophysiological recording of NMDAR, morphological, qualitative and quantitative analysis of synapse number, dendritic spines and behavioral analysis of N-tau transgenic mice performed to give an accurate and global view of the molecular events involved in N-tau modulation of neuronal plasticity will be presented