Dysregulated phosphorylation of Ca 2+/calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer's disease

Lindsay C. Reese, Fernanda Laezza, Randall (Randy) Woltjer, Giulio Taglialatela

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder and the most prevalent senile dementia. The early symptom of memory dysfunction involves synaptic loss, thought to be mediated by soluble amyloid-beta (Aβ) oligomers. These aggregate species target excitatory synapses and their levels correlate with disease severity. Studies in cell culture and rodents have shown that oligomers increase intracellular calcium (Ca 2+), impairing synaptic plasticity. Yet, the molecular mechanism mediating Aβ oligomers' toxicity in the aged brain remains unclear. Here, we apply quantitative immunofluorescence in human brain tissue from clinically diagnosed mild cognitive impaired (MCI) and AD patients to investigate the distribution of phosphorylated (active) Ca 2+/calmodulin-dependent protein kinase-α (p(Thr286)CaMKII), a critical enzyme for activity-dependent synaptic remodeling associated with cognitive function. We show that p(Thr286)CaMKII immunoreactivity is redistributed from dendritic arborizations to neural perikarya of both MCI and AD hippocampi. This finding correlates with cognitive assessment scores, suggesting that it may be a molecular read-out of the functional deficits in early AD. Treatment with oligomeric Aβ replicated the observed phenotype in mice and resulted in a loss of p(Thr286)CaMKII from synaptic spines of primary hippocampal neurons. Both outcomes were prevented by inhibiting the phosphatase calcineurin (CaN). Collectively, our results support a model in which the synaptotoxicity of Aβ oligomers in human brain involves the CaN-dependent subcellular redistribution of p(Thr286)CaMKII. Therapies designed to normalize the homeostatic imbalance of neuronal phosphatases and downstream dephosphorylation of synaptic p(Thr286)CaMKII should be considered to prevent and treat early AD.

Original languageEnglish (US)
Pages (from-to)791-804
Number of pages14
JournalJournal of Neurochemistry
Volume119
Issue number4
DOIs
StatePublished - Nov 2011

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Phosphorylation
Hippocampus
Alzheimer Disease
Oligomers
Brain
Neuronal Plasticity
Calcineurin
Cell culture
Phosphoric Monoester Hydrolases
Amyloid
Neurodegenerative Diseases
Synapses
Cognition
Neurons
Fluorescent Antibody Technique
Plasticity
Toxicity
Cognitive Dysfunction

Keywords

  • Alzheimer's disease
  • amyloid-beta oligomers
  • calcineurin
  • calcium/calmodulin- dependent protein kinase II
  • hippocampus
  • immunofluorescence

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Dysregulated phosphorylation of Ca 2+/calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer's disease. / Reese, Lindsay C.; Laezza, Fernanda; Woltjer, Randall (Randy); Taglialatela, Giulio.

In: Journal of Neurochemistry, Vol. 119, No. 4, 11.2011, p. 791-804.

Research output: Contribution to journalArticle

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