Although several transgenic mouse strains have been developed as models of AB amyloidosis, none of them fully display the hyperphosphorylated tau inclusions and synaptic loss that are important hallmarks of clinical Alzheimer's disease (AD) neuropathology. The best evidence that neurodegeneration occurs in these murine models of amyloid overexpression is the finding that some plaques are surrounded by dystrophic neurites (DNs). Thus, to investigate whether the observed neurodegeneration associated with APP overexpression is dependent on the presence of tau, we mated mice overexpressing human APP (TG2576 transgenic mouse) to our tau knockout mouse (muTau-/-). In this proposal, we intend to explore the role of tau in AD pathology by characterizing the histologic and behavioral phenotype of APP overexpressing transgenic mice in a tau knockout background and comparing this to wild type animals and mice overexpressing APP in a murine and humanized tau background. Clinical evidence suggests an association between traumatic brain injury and development of AD. Evidence suggests that this may be modeled in APP overexpressing mice, in which a mild traumatic brain injury promoted A. deposition and cognitive deficits. We have recently characterized a murine survival model of traumatic brain injury in which mechanically ventilated animals are placed under tight physiological controls and receive a pneumatic impact against the closed skull, producing a more severe brain injury than previously described. We will use this to accelerate the motor and cognitive deficits in these transgenic mice. Clinical observations also suggest that patients on statins (HMG CoA reductase inhibitors) have a lower incidence of developing AD, leading to several ongoing clinical trials in this area. We have also found that administration of simvastatin reduced functional deficits following traumatic brain injury. Based on this, we will administer simvastatin to determine whether this improves the histological or functional outcome following traumatic brain injury in the transgenic lines. Ultimately, this may lead to novel therapeutic strategies that are translatable for use in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AG022230-02
Application #
6757211
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (J3))
Program Officer
Phelps, Creighton H
Project Start
2003-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$185,544
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Lynch, John R; Tang, Wen; Wang, Haichen et al. (2003) APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 278:48529-33