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J. Biol. Chem., Vol. 280, Issue 51, 42088-42096, December 23, 2005

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Defective Tumor Necrosis Factor--dependent Control of Astrocyte Glutamate Release in a Transgenic Mouse Model of Alzheimer Disease^*

Daniela Rossi1, Liliana Brambilla1, Chiara F. Valori, Andrea Crugnola, Giorgio Giaccone, Raffaella Capobianco, Michela Mangieri, Ann E. Kingston¶, Alain Bloc||, Paola Bezzi||, and Andrea Volterra||2

From the Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti, 9, 20133 Milan, Italy, ^||Department of Cell Biology and Morphology, University of Lausanne, Rue du Bugnon, 9, 1005 Lausanne, Switzerland, National Neurological Institute "Carlo Besta", via Celoria 11, 20133 Milan, Italy, and ^¶Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285

The cytokine tumor necrosis factor- (TNF) induces Ca²⁺-dependent glutamate release from astrocytes via the downstream action of prostaglandin (PG) E₂. By this process, astrocytes may participate in intercellular communication and neuromodulation. Acute inflammation in vitro, induced by adding reactive microglia to astrocyte cultures, enhances TNF production and amplifies glutamate release, switching the pathway into a neurodamaging cascade (Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., and Volterra, A. (2001) Nat. Neurosci. 4, 702–710). Because glial inflammation is a component of Alzheimer disease (AD) and TNF is overexpressed in AD brains, we investigated possible alterations of the cytokine-dependent pathway in PDAPP mice, a transgenic model of AD. Glutamate release was measured in acute hippocampal and cerebellar slices from mice at early (4-month-old) and late (12-month-old) disease stages in comparison with age-matched controls. Surprisingly, TNF-evoked glutamate release, normal in 4-month-old PDAPP mice, was dramatically reduced in the hippocampus of 12-month-old animals. This defect correlated with the presence of numerous -amyloid deposits and hypertrophic astrocytes. In contrast, release was normal in cerebellum, a region devoid of -amyloid deposition and astrocytosis. The Ca²⁺-dependent process by which TNF evokes glutamate release in acute slices is distinct from synaptic release and displays properties identical to those observed in cultured astrocytes, notably PG dependence. However, prostaglandin E₂ induced normal glutamate release responses in 12-month-old PDAPP mice, suggesting that the pathology-associated defect involves the TNF-dependent control of secretion rather than the secretory process itself. Reduced expression of DENN/MADD, a mediator of TNF-PG coupling, might account for the defect. Alteration of this neuromodulatory astrocytic pathway is described here for the first time in relation to Alzheimer disease.

Received for publication, April 15, 2005 , and in revised form, October 25, 2005.

^* This work was supported by grants from the European Community (QLK6-1999-02203), Istituto Superiore di Sanità-Italy (National Program on Alzheimer disease), CAssa di RIsparmio delle Province LOmbarde (2001), Ministero dell'Istruzione, dell'Università e della Ricerca-Italy (Cofin 2000 and 2002, Fondo per gli Investimenti della Ricerca di Base 2003), Fonds National Suisse (3100A0-100850/1), Telethon (GGP02052 and GGP05244), Office Federal de l'Education et de la Science (00.0553), and EMBO (ALTF 279–2002). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this study.

² To whom correspondence should be addressed. Tel.: 39-02-50318327; Fax: 39-02-50318284; E-mail: Andrea.Volterra{at}unil.ch.

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