Principal Investigator:

Steven T. DeKosky, MD

Co-Investigator:

Milos Ikonomovic, PhD

Traumatic brain injury (TBI) and Alzheimer’s disease (AD) can exhibit similar clinical and pathological features that suggest common neurodegenerative mechanisms. There is increasing evidence linking AD and TBI, including upregulation of amyloid precursor protein (APP), and its toxic metabolite Aß peptide, in head-injured patients. The current proposal will determine:

1. If controlled cortical impact (CCI) injury produces upregulation of APP and Aß; protein levels;
2. The roles of the inflammatory cytokine IL1ß, NFkB, and caspases in this upregulation;
3. How manipulations which alter IL1ß response, NFkB, or caspase activity affect metabolic processing of APP and the production of Aß; and
4. The effects of these manipulations on apoptosis and behavioral outcomes.

A novel approach will utilize ‘humanized Aß mice’ that produce only human rather than rodent Aß. This will enable use of available and extensively characterized antibodies specific for human APP and Aß, and allow assessment of the toxicity of human Aß in the in vivo rodent model. We will measure IL1ß, NFkB, caspase, APP mRNA and protein, and APP metabolites at various times after TBI in wild type and mutant mice. Experiments will dissect the mechanisms controlling APP metabolism and Aß synthesis and toxicity, by examining the effects of IL1ß receptor antagonist, NFkB inhibitors, and both treatments together, as well as caspase inhibitors, on APP expression and metabolism after TBI. The humanized Aß mouse will allow us to assess the toxicity of human Aß in the animal model, assessing cognitive and motor performance outcome and apoptosis. Several techniques will be used, including ELISA, northern and western blot, in situ hybridization, immunocytochemistry, and immunoprecipitation.

We will parallel these studies clinically by examining the levels of APP and Aß in CSF from human head-injured patients, and in brain tissue from human patients whose injury required emergency surgical resections. Since TBI at the University of Pittsburgh is treated with 48 hours of hypothermia, we will also be able to assess hypothermia effects on CSF APP and Aß, comparing them to normothermic samples previously collected. Preliminary evidence demonstrates that APP and Aß are increased after TBI. The comprehensive studies proposed will provide valuable information regarding APP as a modulator in the post-injury recovery cascade and may suggest new therapeutic targets for both TBI and AD.