Nonfibrillar Abeta 1-42 inhibits glutamate uptake and phosphorylates p38 in human fibroblasts.

Abstract

Alzheimer disease (AD) is the most prevalent neurodegenerative disease, characterized by an increased deposition of β-amyloid (Abeta) within the central nervous system, leading to neuronal death. The availability of effective models, in which confirming novel pathogenic hypotheses and developing therapeutic targets, represents a very important goal for the field of AD. Fibroblasts from these patients may be relevant models in which addressing these issues, as they display biochemical alterations mirroring SNC ones. In this work, fibroblasts obtained from controls were studied after exposure to nonfibrillar Abeta 1-42, showing decreased glutamate uptake, similar to that observed in AD cells, in absence of transporters modifications. Nonfibrillar Abeta 1-42 was able to induce in control cells mitochondrial alterations and p38-phosphorylation, mirroring similar alterations found in AD fibroblasts. Under our experimental conditions, this treatment induced neither apoptosis nor necrosis. To investigate a putative role of p38-modulation in mediating nonfibrillar Abeta 1-42 toxicity, fibroblasts from controls were pretreated with retinoic-acid, and SB203580, a p38-inhibitor. These pretreatments prevented both p38-phosphorylation and glutamate uptake inhibition. Our results suggest that nonfibrillar Abeta 1-42 downregulates glutamate transporters activity interfering with p38-activation and mitochondrial stress. Thus, modulating complex kinase signaling pathway might represent a future therapeutic target in AD.

DOI: 10.1097/WAD.0b013e3181f9860f

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@article{Zoia2011NonfibrillarA1, title={Nonfibrillar Abeta 1-42 inhibits glutamate uptake and phosphorylates p38 in human fibroblasts.}, author={Chiara Paola Zoia and Chiara Riva and Valeria Isella and Paola Proserpio and Alessandro Terruzzi and Silvia Arban and Domenico Salerno and Valeria Cassina and Francesco Mantegazza and Lucio Tremolizzo and Carlo Ferrarese}, journal={Alzheimer disease and associated disorders}, year={2011}, volume={25 2}, pages={164-72} }