CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase

Reactive microglia have been suggested to play a role in the Alzheimer's di sease (AD) process, and previous studies have shown that expression of CD45 , a membrane-bound protein-tyrosine phosphatase (PTP), is elevated in micro glia in AD brain compared with controls. To investigate the possible role o f CD45 in microglial responsiveness to beta-amyloid (A beta) peptides, we f irst co-treated primary cultured microglia with a tyrosine phosphatase inhi bitor [potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 mu M ] and freshly solubilized A beta peptides (1000 nM). Data show synergistic induction of microglial activation as evidenced by tumor necrosis factor al pha (TNF-alpha) production and nitric oxide (NO) release, both of which we show to be dependent on activation of p44/42 mitogen-activated protein kina se (MAPK). Furthermore, co-treatment with phen and A beta peptides results in microglia-induced neuronal cell injury. Stimulation of microglial CD45 b y anti-CD45 antibody markedly inhibits these effects via inhibition of p44/ 42 MAPK, suggesting that CD45 is a negative regulator of microglial activat ion. Accordingly, primary cultured microglia from CD45-deficient mice demon strate hyper-responsiveness to A beta, as evidenced by TNF-alpha release, N O production, and neuronal injury after stimulation with A beta peptides. A s a validation of these findings in vivo, brains from a transgenic mouse mo del of AD [transgenic Swedish APP-overexpressing (Tg APP(sw)) mice] deficie nt for CD45 demonstrate markedly increased production of TNF-alpha compared with Tg APPsw mice. Taken together, these results suggest that therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in s uppressing microglial activation associated with AD.