Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures

• Published in: Neurobiology of aging Vol. 28; no. 9; pp. 1388 - 1395
• Main Authors: Tardito, Daniela, Gennarelli, Massimo, Musazzi, Laura, Gesuete, Raffaella, Chiarini, Stefania, Barbiero, Valentina Sara, Rydel, Russell E, Racagni, Giorgio, Popoli, Maurizio
• Format: Journal Article
• Language: English
• Published: United States 01.09.2007
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Animals, Newborn; Blotting, Western; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Enzyme Activation - drug effects; Hippocampus - drug effects; Organ Culture Techniques; Peptide Fragments - pharmacology; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Threonine - metabolism; Time Factors; Up-Regulation - drug effects
• ISSN: 1558-1497

Recent findings suggested a role for soluble amyloid-beta (Abeta) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Abeta(1-40) on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4h) and long-term (5 days) with Abeta(1-40) (1nM-5microM). Abeta did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr(286) phosphorylation. In contrast, long-term treatment (1nM-microM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10nM (three-fold). Up-regulation of activity was associated with increased expression of the alpha-isoform of CaM kinase II, increased phosphorylation at Thr(286) (activator residue) and decreased phosphorylation at Thr(305-306) (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10nM Abeta(1-40). As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Abeta. Short- and long-term Abeta treatment showed opposite effects on CaM kinase II, suggesting that long-term changes are an adaptation to the kinase early down-regulation. The marked effect of Abeta(1-40) on the kinase suggests that semi-physiological and slowly raising peptide concentrations may have a significant impact on synaptic plasticity in the absence of synaptic loss or neuronal cell death.