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

The long-term goal of this work is to alleviate the burdens that traumatic brain injury (TBI) and Alzheimer's disease (AD) impose on caregivers and affected individuals by providing the knowledge necessary to develop effective preventative or therapeutic strategies for these conditions.

TBI is arguably the most well-established, non-genetic risk factor for dementia, including AD. Military personnel and civilians that experience a TBI are at an increased risk of developing AD and related neurological disorders that can lead to long-term cognitive and behavioral impairments, including dementia, aggression, memory loss, and depression. Over 5 million Americans currently are affected by AD, which is estimated to grow to 13 million by 2050 with a cost of care to treat patients of about $203 billion annually. The prevalence of AD in the Veteran population is the same as in the civilian population; however, the number of affected individuals is expected to increase dramatically, not only as the Veteran population ages, but also because of the increased incidence of TBI. On the histological level, AD and TBI-associated neurodegeneration are characterized by aggregates of the protein tau that modifies its characteristics becoming toxic, suggesting that tau may play role in both of these conditions. In the proposed research project, we will explore the hypothesis that TBI leads to impairments of cell to cell communication underlying memory loss in AD through a modification in the AD protein tau and involvement of amyloid precursor protein (APP), another major protein involved in AD. In preliminary experiments using biochemical methods to isolate tau, and both electrophysiological and behavioral assays, we made the surprising discovery that tau extracted from the brain of shockwave-exposed mice is capable of impairing both cell-to-cell communication and memory in recipient animals that were treated with it. These impairments were similar to the electrophysiological and behavioral changes produced by tau extracted from the brains of humans with AD. In the experiments outlined in this proposal, we will use similar biochemical strategies together with electrophysiological and behavioral methods to:

1) Test the prediction that tau derived from TBI brains produces changes in cell to cell communication associated with AD.

2) Test the prediction that the presence of APP is necessary for tau derived from TBI brains to produce the impairment of cell to cell communication and memory associated with AD.

3) Test the prediction that phosphorylation at the a specific site of the APP intracellular domain, the threonine in position 668, is necessary for tau derived from TBI brains to produce the impairments of synaptic function and memory that are associated with AD.

Identification of a role for the intracellular domain of APP is likely to help finding a therapy that either improves quality of life of people affected by AD (military, Veterans, or civilians), delays the disease or, in the most sought scenario, cures it.