Reactive microglia have been suggested to play a role in aging-related neurodegenerative processes, including the Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), and previous studies have shown that expression of CD45, a membrane-bound protein tyrosine phosphatase (PTP), is elevated in microglia in AD brain compared to controls. We previously found that stimulation of CD45 PTP signaling by anti-CD45 antibody greatly inhibits microglial activation induced by LPS or Abeta peptides, as evidenced by decreased TNF-alpha production, nitric oxide (NO) release, and neuronal injury. Further, these effects are dependent on inhibition of p44/42 mitogen activated protein kinase, an important pro-inflammatory pathway. Accordingly, primary cultured microglial cells from CD45-deficient mice demonstrate hyper-responsiveness to LPS and Abeta treatments, as evidenced by increased TNF-alpha release, NO production, and neuronal injury. As a validation of these findings in vivo, brains from a transgenic mouse model of amyloid deposition deficient for CD45 demonstrate markedly increased production of TNF-alpha and tau phosphorylation (an early marker for neuronal injury) compared to transgenic mice with intact CD45. Altogether, these results suggest that CD45 is a negative regulator of microglial activation, and therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in suppressing microglial activation associated with aging related disorders, such as AD, PD and ALS. Although CD45 expression increases with inflammatory activity, its role is predicted to prevent runaway inflammatory reactions. In this proposal, we hypothesize that CD45 deficient mice will increase activated microglia at an early age, and therefore will show increased neurodegeneration. To test this hypothesis, we plan to fully characterize the role of CD45 in modulation of microglial activation in vitro and in vivo by examining its signaling pathways and resultant effects on microglial phagocytic capability, cytokine profiles and degeneration of cholinergic/dopaminergic neurons, and specifically its impact on aging in Alzheimer transgenic mice, as its effects on AD-like pathology and behavioral changes. This work will be carried out by the following aims. (1) Function of CD45 PTP signaling on microglial activation. (2) Role of CD45 in preventing neurodegeneration. We plan to compare CD45 deficient and sufficient mice at different ages for markers of inflammation and microglial activation. Specifically, these markers of inflammation and microglial activation will be correlated with the behavioral performance of these mice on cognitive function and motor performance tasks. (3) CD45 deficiency will accelerate AD-like pathology and behavioral impairment in an Alzheimer mouse. (4) Administration of blueberry (BB) to CD45 deficient mice will result in reduced microglia-inflammation, increased maturation of neuronal cells and improved cognitive/motor performance.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Florida
United States
Zip Code
Bickford, Paula C; Flowers, Antwoine; Grimmig, Bethany (2017) Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases. Exp Gerontol 94:4-8
Grimmig, Bethany; Kim, Seol-Hee; Nash, Kevin et al. (2017) Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. Geroscience 39:19-32
Tajiri, Naoki; Acosta, Sandra A; Shahaduzzaman, Md et al. (2014) Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 34:313-26
Lee, Daniel C; Ruiz, Claudia R; Lebson, Lori et al. (2013) Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging 34:1610-20
Lee, D C; Rizer, J; Hunt, J B et al. (2013) Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 39:69-85
Ross, Jaime M; Stewart, James B; Hagström, Erik et al. (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501:412-5
Shahaduzzaman, Md; Golden, Jason E; Green, Suzanne et al. (2013) A single administration of human umbilical cord blood T cells produces long-lasting effects in the aging hippocampus. Age (Dordr) 35:2071-87
Olson, Linus; Faulkner, Stuart; Lundströmer, Karin et al. (2013) Comparison of three hypothermic target temperatures for the treatment of hypoxic ischemia: mRNA level responses of eight genes in the piglet brain. Transl Stroke Res 4:248-57
Morganti, Josh M; Nash, Kevin R; Grimmig, Bethany A et al. (2012) The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease. J Neurosci 32:14592-601
Li, Qingyou; Lebson, Lori; Lee, Daniel C et al. (2012) Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load. J Neuroimmune Pharmacol 7:202-14

Showing the most recent 10 out of 317 publications