Role of Amyloid Precursor Protein in Alzheimer's Disease-Related Impairment of Synaptic Function and Memory Induced by Abnormal Tau Following TBI

In the proposed research project we will test the hypothesis that tau derived from TBI brains produces a similar impairment in synaptic function and memory as tau from AD brains and thereby identify the mechanisms whereby tau derived from TBI leads to the development of abnormal synaptic function and memory that are associated with AD. Specifically, we will address the following aims: Aim 1) To test the prediction that tau derived from TBI brains produces changes in synaptic plasticity, neurotransmission, and neuronal excitability that are associated with AD. Aim 2) To test the prediction that the presence of amyloid-precursor protein (APP) is necessary for tau derived from TBI brains to produce the impairments of synaptic function and memory associated with AD. Aim 3) To test the prediction that phosphorylation at the APP-Thr668 site is necessary for tau derived from TBI brains to produce the impairments of synaptic function and memory that are associated with AD. During the last year we have worked on the first aim. We have found that similar to AD tau, administration of tau purified from shockwave-exposed mice onto wild-type mice markedly reduces certain forms of short-term plasticity. Additional, planned electrophysiological experiments are ongoing that will allow us to complete aim 1 and provide new insights into the similarities in tau changes between TBI and AD.