The overarching goal of this research project is to understand how the innate immune system in the brain participates in the generation of Alzheimer's disease. To accomplish this goal, we will use novel mouse models of AD that we have developed. These mice show AD-like pathology including (1) amyloid deposits, (2) hyperphosphorylated and aggregated native mouse tau in the somatodendritic neuronal compartment, (3) neuronal loss, 4) robust cognitive deficits and 5) neurovascular unit damage. The AD-like disease phenotype was generated by crossing mice that express mutated human APP with mice that lack a functional nitric oxide synthase 2 (NOS2) gene to produce a bigenic hAPP/NOS2-/- mouse. By reducing NO levels in mice during an immune response to those levels more equivalent in human, these mice express a full spectrum of AD-like pathology. Preliminary data from the APPSw/NOS2-/- mice that show a full spectrum of AD-like pathology demonstrate an inflammatory gene profile highly reminiscent of the immune profile in brains of humans with AD. In both bigenic mice and AD brain, a complex immune activation state is observed that includes genes that code for classical pro-inflammatory factors and genes that code for anti-inflammatory factors, repair factors (alternative activation) or down-regulatory responses (acquired deactivation). Our overarching hypothesis is that the immune state plays a causal role in the disease process in AD. We hypothesize that resident immune cells undergo complex changes in immune properties in response to A? that vary throughout the life cycle of the disease. We also hypothesize that these immune changes alter the levels of specific AD pathology or alter disease progression. We will study the brain's immune status by 1) identifying changes in the brain's innate immune system as a function of the level of AD pathology and of disease progression using specific candidate markers of immune activation states (classical, alternative and acquired deactivation), 2) investigating the causal role of the innate immune activation state in disease pathogenesis by using interventions that will modify activation profiles and 3) investigating the cytotoxic potential of TNFa, the most likely immune-regulated cytokine to damage neurons in AD. PUBLIC HEALTH REVELANCE: This project will examine the role of the brain's innate immune state in generating the neuropathology associated with chronic neurodegenerative diseases such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031845-05
Application #
8531803
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Petanceska, Suzana
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$287,581
Indirect Cost
$103,234
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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Hoos, Michael D; Richardson, Brenna M; Foster, Matthew W et al. (2013) Longitudinal study of differential protein expression in an Alzheimer's mouse model lacking inducible nitric oxide synthase. J Proteome Res 12:4462-77
Colton, Carol A (2013) Microglial-neuronal interactions during neurodegenerative diseases. J Neuroimmune Pharmacol 8:4-6
Wink, David A; Hines, Harry B; Cheng, Robert Y S et al. (2011) Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 89:873-91
Wilcock, Donna M; Zhao, Qun; Morgan, Dave et al. (2011) Diverse inflammatory responses in transgenic mouse models of Alzheimer's disease and the effect of immunotherapy on these responses. ASN Neuro 3:249-58
Wilcock, Donna M; Morgan, Dave; Gordon, Marcia N et al. (2011) Activation of matrix metalloproteinases following anti-A? immunotherapy; implications for microhemorrhage occurrence. J Neuroinflammation 8:115