The Na/Caexchanger in Alzheimer's disease.

As a pivotal player in regulating sodium (Na) and calcium (Ca) homeostasis and signalling in excitable cells, the Na/Ca exchanger (NCX) is involved in many neurodegenerative disorders in which an imbalance of intracellular Ca and/or Na concentrations occurs, including Alzheimer's disease (AD). Although NCX has been mainly implicated in neuroprotective mechanisms counteracting Ca dysregulation, several studies highlighted its role in the neuronal responses to intracellular Na elevation occurring in several pathophysiological conditions. Since the alteration of Na and Ca homeostasis significantly contributes to synaptic dysfunction and neuronal loss in AD, it is of crucial importance to analyze the contribution of NCX isoforms in the homeostatic responses at neuronal and synaptic levels. Some studies found that an increase of NCX activity in brains of AD patients was correlated with neuronal survival, while other research groups found that protein levels of two NCX subtypes, NCX2 and NCX3, were modulated in parietal cortex of late stage AD brains. In particular, NCX2 positive synaptic terminals were increased in AD cohort while the number of NCX3 positive terminals were reduced. In addition, NCX1, NCX2 and NCX3 isoforms were up-regulated in those synaptic terminals accumulating amyloid-beta (Aβ), the neurotoxic peptide responsible for AD neurodegeneration. More recently, the hyperfunction of a specific NCX subtype, NCX3, has been shown to delay endoplasmic reticulum stress and apoptotic neuronal death in hippocampal neurons exposed to Aβ insult. Despite some issues about the functional role of NCX in synaptic failure and neuronal loss require further studies, these findings highlight the putative neuroprotective role of NCX in AD and open new strategies to develop new druggable targets for AD therapy.