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J. Biol. Chem., Vol. 283, Issue 44, 29950-29960, October 31, 2008

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Nonspecific Interaction of Prefibrillar Amyloid Aggregates with Glutamatergic Receptors Results in Ca²⁺ Increase in Primary Neuronal Cells^*

Francesca Pellistri, Monica Bucciantini^¶, Annalisa Relini, Daniele Nosi^||, Alessandra Gliozzi, Mauro Robello¹, and Massimo Stefani^¶

From the Department of Physics, University of Genoa, Via Dodecaneso, 33, I-16146 Genoa, Research Centre on the Molecular Basis of Neurodegeneration, ^¶Department of Biochemical Sciences, University of Florence, Viale Morgagni, 50, 50134 Florence, and the ^||Department of Anatomy, Histology, and Forensic Medicine, University of Florence, Florence 50134, Italy

It is widely reported that the Ca²⁺ increase following nonspecific cell membrane permeabilization is among the earliest biochemical modifications in cells exposed to toxic amyloid aggregates. However, more recently receptors with Ca²⁺ channel activity such as -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl D-aspartate (NMDA), ryanodine, and inositol 1,4,5-trisphosphate receptors have been proposed as mediators of the Ca²⁺ increase in neuronal cells challenged with β-amyloid peptides. We previously showed that prefibrillar aggregates of proteins not associated with amyloid diseases are toxic to exposed cells similarly to comparable aggregates of disease-associated proteins. In particular, prefibrillar aggregates of the prokaryotic HypF-N were shown to be toxic to different cultured cell lines by eliciting Ca²⁺ and reactive oxygen species increases. This study was aimed at assessing whether NMDA and AMPA receptor activations could be considered a generic feature of cell interaction with amyloid aggregates rather than a specific effect of some aggregated protein. Therefore, we investigated whether NMDA and AMPA receptors were involved in the Ca²⁺ increase following exposure of rat cerebellar granule cells to HypF-N prefibrillar aggregates. We found that the intracellular Ca²⁺ increase was associated with the early activation of NMDA and AMPA receptors, although some nonspecific membrane permeabilization was also observed at longer times of exposure. This result matched a significant co-localization of the aggregates with both receptors on the plasma membrane. Our data support the possibility that glutamatergic channels are generic sites of interaction with the cell membrane of prefibrillar aggregates of different peptides and proteins as well as the key structures responsible for the resulting early membrane permeabilization to Ca²⁺.

Received for publication, May 26, 2008 , and in revised form, July 31, 2008.

^* This work was supported by Italian MUR Grants 2005053998_001 and _005, Fondazione CARIGE, and Ente Cassa di Risparmio di Firenze. 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 To whom correspondence should be addressed: Dept. di Fisica, Universitàdi Genova, Via Dodecaneso, 33, I-16146 Genoa, Italy. Tel.: 39-010-3536316; Fax: 39-010-314218; E-mail: robello{at}fisica.unige.it.

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