Long-term soluble Aβ1-40 activates CaM kinase II in organotypic hippocampal cultures

Daniela Tardito, Massimo Gennarelli, Laura Musazzi, Raffaella Gesuete, Stefania Chiarini, Valentina Sara Barbiero, Russell E. Rydel, Giorgio Racagni, Maurizio Popoli

Research output: Contribution to journalArticlepeer-review

Abstract

Recent findings suggested a role for soluble amyloid-β (Aβ) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Aβ1-40 on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4 h) and long-term (5 days) with Aβ1-40 (1 nM-5 μM). Aβ did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr286 phosphorylation. In contrast, long-term treatment (1 nM-5 μM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10 nM (three-fold). Up-regulation of activity was associated with increased expression of the α-isoform of CaM kinase II, increased phosphorylation at Thr286 (activator residue) and decreased phosphorylation at Thr305-306 (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10 nM Aβ1-40. As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Aβ. Short- and long-term Aβ 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 Aβ1-40 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.

Original languageEnglish
Pages (from-to)1388-1395
Number of pages8
JournalNeurobiology of Aging
Volume28
Issue number9
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Alzheimer
  • Amyloid
  • CaM kinase II
  • Glutamate
  • Protein phosphorylation
  • Synaptic plasticity

ASJC Scopus subject areas

  • Clinical Neurology
  • Biological Psychiatry
  • Developmental Neuroscience
  • Neurology
  • Psychology(all)

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