The Role of Aβ-Induced Calcium Dysregulation in the Pathogenesis of Alzheimer's Disease

Although many of the biochemical mechanisms which regulate production or clearance of the amyloid-beta protein (A beta) of Alzheimer's disease (AD) are now well understood, the mechanism of A beta neurotoxicity remains unclear. A number of studies have shown that A beta can disrupt neuronal Ca2+ homeostasis by inducing influx of extracellular Ca2+ into the neuronal cytoplasm. Ca2+ is known to play an important role in neuronal excitability, synaptic plasticity and neurotoxicity. Therefore, A beta-induced Ca2+ dysregulation may contribute to many of the cognitive and neuropathologic features of AD. In vitro studies show that A beta can increase ion permeability in lipid membranes. This increased permeability is reportedly associated with the formation of artificial ion pores formed from A beta oligomers. However, a number of other studies show that A beta can activate endogenous ion channels on the cell surface. There is also increasing evidence that presenilin mutations alter intracellular Ca2+ stores. It is likely that elucidation of the mechanism by which A beta and presenilin cause Ca2+ dysregulation in neurons will help to identify new drug targets for the treatment of AD.