Affiliations: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
Correspondence:
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Correspondence to: C.W. Xie, Department of Psychiatry, Semel Institute for Neuroscience, University of California Los Angeles, 760 Westwood Plaza, Box 77, Los Angeles, CA 90024, USA. Tel.: +1 310 206 0083; Fax: +1 310 206 2946; E-mail: cxie@mednet.ucla.edu.
Abstract: Amyloid-β (Aβ) peptide-induced impairment of hippocampal synaptic plasticity is considered an underlying mechanism for memory loss in the early stages of Alzheimer's disease and its animal models. We previously reported inhibition of long-term potentiation (LTP) and miniature excitatory postsynaptic currents by oligomeric Aβ1–42 at hippocampal synapses. While multiple cellular mechanisms could be involved in Aβ-induced synaptic dysfunction, blockade of activity-dependent autophosphorylation of Ca2+ and calmodulin-dependent protein kinase II (CaMKII) appeared to be a major component of Aβ action in our studies. The present study further tested this hypothesis and examined the therapeutic potential of trkB receptor-acting neurotrophins in rescuing Aβ-induced synaptic and signaling impairments. As expected, treatment of rat hippocampal slices with Aβ1–42 significantly reduced LTP in the Schaffer collateral-CA1 pathway and dentate medial perforant path. LTP-associated CaMKII activation and AMPA receptor phosphorylation were blocked by Aβ1–42 at the same concentration that inhibited LTP. Aβ-induced LTP impairment, however, was prevented when slices were co-treated with neurotrophin 4 (NT4). Western blotting and immunohistochemical analyses confirmed that treatment with NT4 or brain-derived neurotrophic factor, another trkB-acting neurotrophin, could oppose Aβ action, enhancing autophosphorylation of CaMKII, and AMPA receptor phosphorylation at a CaMKII-dependent site. These findings support the view that CaMKII is a key synaptic target of Aβ toxicity as well as a potential therapeutic site of neurotrophins for Alzheimer's disease.
Keywords: Amyloid-β, calcium and calmodulin-dependent protein kinase II, hippocampus, long-term potentiation, neurotrophins
