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Amyloid Prevents Activation of Calcium/Calmodulin-Dependent Protein Kinase II and AMPA Receptor Phosphorylation During Hippocampal Long-Term Potentiation

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine and Neuropsychiatric Institute, University of California, Los Angeles, California 90024

Submitted 9 May 2004; accepted in final form 10 June 2004

Accumulation of amyloid -peptides (A) in the brain has been linked with memory loss in Alzheimer's disease and its animal models. However, the synaptic mechanism by which A causes memory deficits remains unclear. We previously showed that acute application of A inhibited long-term potentiation (LTP) in the hippocampal perforant path via activation of calcineurin, a Ca²⁺-dependent protein phosphatase. This study examined whether A could also inhibit Ca²⁺/calmodulin dependent protein kinase II (CaMKII), further disrupting the dynamic balance between protein kinase and phosphatase during synaptic plasticity. Immunoblot analysis was conducted to measure autophosphorylation of CaMKII at Thr²⁸⁶ and phosphorylation of the GluR1 subunit of AMPA receptors in single rat hippocampal slices. A high-frequency tetanus applied to the perforant path significantly increased CaMKII autophosphorylation and subsequent phosphorylation of GluR1 at Ser⁸³¹, a CaMKII-dependent site, in the dentate area. Acute application of A_1–42 inhibited dentate LTP and associated phosphorylation processes, but was without effect on phosphorylation of GluR1 at Ser⁸⁴⁵, a protein kinase A-dependent site. These results suggest that activity-dependent CaMKII autophosphorylation and AMPA receptor phosphorylation are essential for dentate LTP. Disruption of such mechanisms could directly contribute to A-induced deficits in hippocampal synaptic plasticity and memory.

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