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

Abstract

Accumulation of amyloid β-peptides (Aβ) in the brain has been linked with memory loss in Alzheimer's disease and its animal models. However, the synaptic mechanism by which Aβ causes memory deficits remains unclear. We previously showed that acute application of Aβ inhibited long-term potentiation (LTP) in the hippocampal perforant path via activation of calcineurin, a Ca²⁺-dependent protein phosphatase. This study examined whether Aβ 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 Aβ_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 Aβ-induced deficits in hippocampal synaptic plasticity and memory.