Dysfunction of Na⁺/Ca²⁺ exchangers is associated with cognitive decline in Alzheimer’s disease

Abstract

Na⁺/Ca²⁺ exchanger (NCX) is mainly expressed in the plasma membrane and mediates electrogenical exchange of one Ca²⁺ for three Na⁺, depending on the electrochemical gradients across the plasma membrane. NCX has three different isoforms (NCX1, NCX2, NCX3) encoded by distinct genes in mammals. Here, we report that NCX2 and NCX3 protein levels are relatively reduced in hippocampal CA1 of Alzheimer’s disease model mice. Likewise, NCX2^+/− or NCX3^+/− mice exhibited impaired hippocampal LTP and memory-related behaviors. In immunoblot analyses, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in hippocampal CA1 of NCX2^+/− mice compared to wild-type mice. By contrast, NCX2^+/− mice was correlated with elevated calcineurin (CaN) activity and rescued by treatment with the calcineurin inhibitor FK506. Taken together, the imbalance of CaMKII and CaN activities with concomitant LTP impairment likely accounts for the learning disability observed in NCX2^+/− mice.