Traumatic brain injury (TBI) is an extremely debilitating for the aging community as studies have found both increased incidence and severity within this population. Furthermore, TBI is the most predictive environmental factor for development of Alzheimer?s disease and other dementia related illnesses. The importance of age as a prognostic factor after TBI has long been recognized but limited studies has been devoted to understanding mechanisms that regulate secondary events that occur after the initial trauma. Even less research has been aimed at studying the mechanisms of cognitive loss in the elderly. The critical changes that affect cognition take place over a long period of time following the initial insult and the innate immune system activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function. In this proposal I will investigate the respective contribution of infiltrating macrophages and activated resident microglia in production of a neurotoxic and inflammatory milieu following TBI in an aging animal. Preliminary data for this proposal has found that TBI causes an exacerbated and prolonged CCR2+ macrophage infiltration in the aging brain when compared to young. The increased recruitment of peripherally derived monocytes significantly augments TBI-induced neuroinflammatory sequelae characterized by protracted activation of both microglia and macrophages as well as decreased synaptic integrity which may potentiate exacerbated injury-induced cognitive dysfunction observed in old animals. All together these findings demonstrate that, in the aging brain, peripherally derived macrophages have a distinct contribution to the TBI- related inflammatory response. In this proposal, I will identify the temporal relationships between macrophage infiltration, myeloid cell localization and inflammatory profiles in an aging animal after injury. Furthermore, I will investigate if blockade of macrophage infiltration can mitigate injury-induced neurotoxicity (dendritic spine loss and decreased synaptic integrity) thereby alleviating cognitive deficits. Findings from this work will advance mechanistic understanding of secondary mechanisms associated with TBI and test a pharmacological agent (already in clinical trials) for treatment of TBI-induced cognitive deficits in an aging animal.

Public Health Relevance

Clinically, traumatic brain injury (TBI) is one of the most powerful environmental risk factors for the development of Alzheimer?s disease (AD) and dementia and age is a significant factor in both the risk and the incidence of acquired brain injury. Preliminary data from the lab found that peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory profile and cognitive deficits in aging animals. This proposal will identify the kinetics of age-related injury-induced inflammatory responses and investigate the possibility of inhibition of macrophage infiltration as a treatment strategy for TBI-induced cognitive deficits in an aging animal with the potential to develop clinically relevant treatment strategies for the aging population at high-risk for the development of AD and dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG054126-01A1
Application #
9329262
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Krukowski, Karen; Feng, Xi; Paladini, Maria Serena et al. (2018) Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits. Sci Rep 8:7857
Chou, Austin; Krukowski, Karen; Jopson, Timothy et al. (2017) Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A 114:E6420-E6426
Guglielmetti, Caroline; Chou, Austin; Krukowski, Karen et al. (2017) In vivo metabolic imaging of Traumatic Brain Injury. Sci Rep 7:17525