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Date of this Version



FASEB J. 20, 670–682 (2006)


U.S. Government Work


Enhanced expression of tumor necrosis

factor (TNF) -α, is associated with the neuropathological

effects underlying disease-, trauma- and chemically

induced neurodegeneration. Previously, we have shown

that deficiency of TNF receptors protects against

MPTP-induced striatal dopaminergic neurotoxicity,

findings suggestive of a role for TNF-α in neurodegeneration.

Here, we demonstrate that deficiency of TNF

receptors suppresses microglial activation and alters

the susceptibility of brain regions to MPTP. MPTPinduced

expression of microglia-derived factors,

TNF-α, MCP-1, and IL-1α, preceded the degeneration

of striatal dopaminergic nerve terminals and astrogliosis,

as assessed by loss of striatal dopamine and TH,

and an increase in striatal GFAP. Pharmacological

neuroprotection with the dopamine reuptake inhibitor,

nomifensine, abolished striatal dopaminergic neurotoxicity

and associated microglial activation. Similarly,

in mice lacking TNF receptors, microglial activation

was suppressed, findings consistent with a role for

TNF-α in striatal MPTP neurotoxicity. In the hippocampus,

however, TNF receptor-deficient mice showed exacerbated

neuronal damage after MPTP, as evidenced by

Fluoro Jade-B staining (to identify degenerating neurons)

and decreased microtubule-associated protein-2 (MAP-2)

immunoreactivity. These effects were not accompanied

by microglial activation, but were associated with increased

oxidative stress (nitrosylation of tyrosine residues).

These findings suggest that TNF-α exerts a neurotrophic/

neuroprotective effect in hippocampus. The

marked differences we observed in the regional density,

distribution and/or activity of microglia and microgliaderived

factors may influence the region-specific role for

this cell type. Taken together, our results are indicative of

a region-specific and dual role for TNF-α in the brain: a

promoter of neurodegeneration in striatum and a protector

against neurodegeneration in hippocampus.OSriram,

K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster,

M. I., O'Callaghan, J. P. Deficiency of TNF receptors

suppresses microglial activation and alters the susceptibility

of brain regions to MPTP-induced neurotoxicity: role

of TNF-α.