PROJECT 2

University Of South Florida, Tampa FL

Investigators

Linked publications & trials

Abstract

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