Elsevier

Neuroscience

Volume 153, Issue 3, 15 May 2008, Pages 618-633
Neuroscience

Cellular neuroscience
Differential activation of mitogen-activated protein kinase signalling pathways in the hippocampus of CRND8 transgenic mouse, a model of Alzheimer's disease

https://doi.org/10.1016/j.neuroscience.2008.02.061Get rights and content

Abstract

Transgenic Centre for Research in Neurodegenerative Diseases 8 (TgCRND8) mice expressing a double mutant form of human amyloid precursor protein represent a good model of Alzheimer's disease, and can be useful to clarify the involvement of mitogen-activated protein kinases (MAPK) dysregulation in the pathophysiology of this neurodegenerative disorder. Activation of extracellular regulated kinase (ERK) 1/2, jun kinase (JNK) and p38MAPK was studied in the hippocampus of 7-month-old TgCRND8 mice by immunohistochemistry and Western blot analysis using antibodies selective for the phosphorylated, and thus active, forms of the enzymes. We demonstrated that the three main MAPK pathways were differentially activated in cells of the hippocampus of TgCRND8 mice in comparison to wild type (Wt) littermates, p38MAPK and JNK being more activated, while ERK less activated. p38MAPK was significantly activated in microglia, astrocytes and neurons, around and distant from the plaques. JNK was highly activated in cells closely surrounding the plaques. No difference was observed in the activation of the two major bands of JNK, at a molecular weight of 46 kDa and 54 kDa. These data indicate the possible involvement of p38MAPK and JNK pathways dysregulation in the pathogenesis of Alzheimer's disease. The ERK2 isoform of the ERK pathway was less activated in the hippocampal dentate gyrus of Tg mice in basal conditions. Furthermore activation of the ERK pathway by ex vivo cholinergic stimulation with carbachol caused significantly higher activation of ERK in the hippocampus of Wt mice than in Tg mice. These findings may pose a molecular basis for the memory disruption of Alzheimer's disease, since proper functioning of the basal forebrain cholinergic neurons and of ERK2 is critical for memory formation.

Section snippets

Animals

Tg heterozygous TgCRND8 mice with a (C57)/(C57/C3H) genetic background and non-Tg littermates hybrid (C57)/(C57/C3H) wild type (Wt) control mice of 7 months of age were used. The mice were obtained from the laboratory of Prof. P. St. George-Hyslop (CRND, Toronto, ON, Canada) and were bred in the Centre for Laboratory Animals, University of Florence, Italy. The mice were housed in macrolon cages with ad libitum food and water and maintained on a 12-h light/dark cycle at 23 °C room temperature

Results

As reported in previous papers (Bellucci et al 2006, Bellucci et al 2007), TgCRND8 mice at 7 months of age show the presence of numerous β-amyloid deposit in the hippocampus and other brain areas, as well as astrocytes and microglia activation, inflammatory markers, nitrosative stress, neuronal damage, hyperphosphorylated tau, cholinergic dysfunction and impairment in learning and memory functions. Therefore, our work was aimed at understanding the intracellular pathways that might be switched

Discussion

Three main mammalian MAPK subfamilies have been described: ERK1,2, JNK, and p38MAPK kinase (Pearson et al., 2001). MAPKs are implicated in various cellular processes (Raman et al., 2007), and dysfunction of specific MAPKs is associated with diseases such as cancer and immunological disorders. In the nervous system, as well as in other tissues, activation of JNK and p38MAPK has often been correlated with death in various cell types, including neurons (Xia et al 1995, Kummer et al 1997,

Acknowledgments

This research was partly funded by PRIN 2005 and partly by Università di Firenze (ex 60%).

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    Present address: Division of Pharmacology, Department of Biomed. and Biotechnol. Sci., University of Brescia, Viale Europa 11, 25123 Brescia, Italy (A. Bellucci).

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