Role of calcium in the pathogenesis of Alzheimer’s disease and transgenic models

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the elderly that is characterized by memory loss. Neuropathologically, the AD brain is marked by an increased Aβ burden, hyperphosphorylated tau aggregates, synaptic loss, and inflammatory responses. Disturbances in calcium homeostasis are also one of the earliest molecular changes that occur in AD patients, alongside alterations in calcium-dependent enzymes in the post-mortem brain. The sum of these studies suggests that calcium dyshomeostasis is an integral part of the pathology, either influencing Aβ production, mediating its effects or both. Increasing evidence from in vitro studies demonstrates that the Aβ peptide could modulate a number of ion channels increasing calcium influx, including voltage-gated calcium and potassium channels, the NMDA receptor, the nicotinic receptor, as well as forming its own calcium-conducting pores. In vivo evidence has shown that Aβ impairs both LTP and cognition, whereas all of these ion channels cluster at the synapse and underlie synaptic transmission and hence cognition. Here we consider the evidence that Aβ causes cognitive deficits through altering calcium homeostasis at the synapse, thus impairing synaptic transmission and LTP. Furthermore, this disruption appears to occur without overt or extensive neuronal loss, as it is observed in transgenic mouse models of AD, but may contribute to the synaptic loss, which is an early event that correlates best with cognitive decline.