Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

Abstract

The neurotoxic effects of activated microglia in neurodegenerative diseases are well established. We recently provided evidence that chromogranin A (CGA), a multifunctional protein localized in dystrophic neurites and in senile plaques, induces an activated phenotype and secretion of neurotoxins by rat microglia in culture. In the present study, we focused on the mechanisms underlying neuronal degeneration triggered by CGAactivated microglia. We found that neuronal death exhibits apoptotic features, characterized by the externalization of phosphatidylserine and the fragmentation of DNA. Microglial neurotoxins markedly stimulate the phosphorylation and activity of neuronal p38 mitogenactivated protein kinase and provoke the release of mitochondrial cytochrome c, which precedes apoptosis. Inhibition of p38 kinase with SB 203580 partially protects neurons from death induced by CGA-activated microglia. Furthermore, neurons are also protected by Fas-Fc, which antagonizes the interactions between the death receptor Fas and its ligand FasL and by cell-permeable peptides that inhibit caspases 8 and 3. Thus, CGA triggers the release of microglial neurotoxins that mobilize several death-signaling pathways in neurons. Our results further support the idea that CGA, which is upregulated in many neuropathologies, represents a potent endogeneous inflammatory factor possibly responsible for neuronal degeneration.

β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation

“…p38 MAPK activation in neurons was similar in APP751 and WT mice, indicating that this neuronal activation is unlikely to have a role in the increased ischemic vulnerability seen in APP751 mice. However, it is well possible that inhibition of p38 MAPK pathway is beneficial in ischemic injury in general because p38 MAPK activation can promote apoptotic neuronal death (48)(49)(50). In agreement with this idea, treatment with the specific p38 MAPK inhibitor resulted in a slight reduction of infarct size in WT mice, a finding previously reported in rat ischemia model (51).…”

Stimulation of Microglial Metabotropic Glutamate Receptor mGlu2 Triggers Tumor Necrosis Factor α-Induced Neurotoxicity in Concert with Microglial-Derived Fas Ligand

“…Microglia constitutively express FasL at low levels in normal human white matter (Dowling et al, 1996;Bechmann et al, 1999), and microglial activation results in increased expression and release of FasL (Spanaus et al, 1998;Badie et al, 2000;Niinobu et al, 2000;Ciesielski-Treska et al, 2001;Terrazzino et al, 2002). Accordingly, the N9 microglial cell line and primary cultured microglia were found to express FasL.…”

Structural and Biological Characterization of Chromofungin, the Antifungal Chromogranin A-(47–66)-derived Peptide

“…1 H NMR Analysis of Synthetic Peptide CGA- (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66))-A lyophilized sample of 4 mg of CGA-(47-66) was dissolved in 600 l of aqueous 20 mM sodium acetate-d 6 buffer (pH 5.0), 50 mM KCl with the addition of deuterated trifluoroethanol (TFE-d 3 ) to yield 50% (v/v) solution. The final peptide concentration was 3 mM.…”