Traumatic brain injury (TBI) is a very common injury in civilian as well as military populations in the United States and a large number of those that survive live with permanent TBI related disabilities. Notably, individuals exposed to TBI are at a greatly increased risk for developing a number of neurodegenerative diseases termed tauopathies, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). More specifically, TBI promotes the intracellular aggregation of hyperphosphorylated, microtubule- associated protein tau (MAPT) into neurofibrillary tangles (NFTs) in both CTE and AD. One of the earliest and hallmark features of TBI is induction of neuroinflammation, including infiltration of peripheral monocytes into the site of injury and activation of resident brain microglia. Several lines of evidence from the literature and from our laboratories suggest that altered monocyte infiltration and microglial activation may be directly involved in the pathogenesis of MAPT pathologies. However, assessing the exact role of these cells in TBI-induced MAPT pathologies has proven exceedingly difficult due to the lack of reliable methods to distinguish monocytes and activated microglia within the brain in accurate genetic models of MAPT pathologies. The primary hypothesis to be tested in the current studies is that TBI induces infiltration of peripheral monocytes as well as acute and local activation of brain microglia within the injured brain and that these two cell types play roles distinct from each othe in inducing MAPT phosphorylation and aggregation leading to chronic pathological conditions that pre-dispose individuals exposed to TBI to develop tauopathies later in life. The objectives of this exploratory research grant are to assess the role of infiltrating monocytes and activated microglia in the development of MAPT pathologies following TBI utilizing unique genetic models that fluorescently tag monocytes (CCR2-RFP) and microglia (CX3CR1-GFP), genomic-based mouse models of MAPT (hTau) pathologies and genetic models in which infiltration of monocytes is blocked (CCR2 deficiency). The results of this study will be critical for future preclinical studies designed to therapeutically target either monocytes or microglia to block the effects of TBI on downstream MAPT pathologies.
The specific aims of the proposal are: 1. Determine the effect of both mild and moderate TBI on infiltration of peripheral monocytes, activation of microglia and MAPT pathology, cognitive function and neurodegeneration in control and hTau mice. 2. Determine the role of infiltrating monocytes in TBI Induced MAPT pathologies in hTau mice.

Public Health Relevance

Numerous studies have demonstrated that TBI promotes the later development of neurodegenerative disease pathologies, including intracellular phosphorylation and aggregation of MAPT. Increasing evidence suggests that altered neuroinflammation, including infiltration of peripheral monocytes and activation of brain resident microglia is an early feature observed following TBI that could directly contribute to the development of MAPT pathologies. However, the exact role of either infiltration of monocytes or activation of microglia in the development of TBI induced MAPT pathology remains unclear. The current studies seek to examine the role of infiltration of monocytes and activation of microglia i the development of MAPT pathologies using unique genetic models in which monocytes and microglia are genetically tagged, monocyte infiltration is blocked and a genomic-based mouse model of MAPT pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082798-01A1
Application #
8611051
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (03))
Program Officer
Hicks, Ramona R
Project Start
2013-08-01
Project End
2015-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$237,750
Indirect Cost
$87,750
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S et al. (2014) Ontogeny and functions of central nervous system macrophages. J Immunol 193:2615-21