Chronic inflammatory reactions in the brain, has been implicated to play a role in age-related neurodegenerative disorder's, such as Alzheimer's disease (AD). In AD, glial cells in the brain are alerted by the innate immune receptors on the glial cell surface following A? deposition, resulting in activation, phenotypic transformation and release of soluble inflammatory mediators by the glial cells. Some of these inflammatory mediators can be directly toxic to neurons and therefore they have been accused in driving neurodegeneration. Furthermore, in the case of AD, it is hypothesized that these inflammatory cytokines can potentially alter APP processing and A? clearance mechanisms, creating "feedback loops", that promote further A? accumulation. However, we have now generated a wealth of data suggesting that over-expression of inflammatory cytokines (e.g., IL-6, IFN3 and TNF1) does not significantly alter APP levels, APP processing or steady state A? generation in vivo. Rather, all three inflammatory cytokines have a beneficial effect, i.e., they significantly "attenuate" amyloid deposition when expressed early in the disease process and have no effect (neither increase nor decrease) on amyloid deposition when expressed in older mice with significant pre-existing amyloid burdens. In contrast, AAV mediated over-expression of anti-inflammatory cytokine IL-10 led to significantly increased amyloid deposition and exacerbated cognitive deficits in APP transgenic mice (details in Specific Aim 2). Thus, depending on the timing and context, the actions of individual cytokines may produce divergent and unexpected effects during the disease process. Growing evidence now suggests that neural- immune interactions in the brain are intricately connected, complex and engage in significant crosstalk to maintain brain homeostasis and protect the brain. In AD, the role of these complex neural-glial interactions and immune responses in the brain are largely unresolved. In this proposal, we will take advantage of our AAV system to explore the effects of individual cytokines and chemokines particularly as it relates to AD-associated pathologies. The studies outlined in this proposal will provide insight into how specific neuro-inflammatory and neuro-modulatory reactions affect amyloid deposition and microtubule -associated protein tau pathology, the two hallmark pathological features of AD.

Public Health Relevance

This study will use mouse models of Alzheimer's disease (AD) to systematically evaluate the role of the neural- immune responses in AD brain. These studies will provide insight into the role of inflammation on AD pathologies, and potentially lead to the development of novel therapeutic approaches for treating AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032991-02
Application #
8231564
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$285,975
Indirect Cost
$101,475
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Chakrabarty, Paramita; Ceballos-Diaz, Carolina; Lin, Wen-Lang et al. (2011) Interferon-ýý induces progressive nigrostriatal degeneration and basal ganglia calcification. Nat Neurosci 14:694-6
Chakrabarty, Paramita; Herring, Amanda; Ceballos-Diaz, Carolina et al. (2011) Hippocampal expression of murine TNFýý results in attenuation of amyloid deposition in vivo. Mol Neurodegener 6:16