Affiliations: Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia
Correspondence:
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Corresponding author: Prof. David H. Small, Private Bag 24, University of Tasmania, Hobart 7001, Tasmania, Australia. Tel.: +61 3 62267348; Fax: +61 3 62262589; E-mail: [email protected].
Abstract: Although many of the biochemical mechanisms which regulate production or clearance of the amyloid-β protein (Aβ) of Alzheimer's disease (AD) are now well understood, the mechanism of Aβ neurotoxicity remains unclear. A number of studies have shown that Aβ 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, Aβ-induced Ca2+ dysregulation may contribute to many of the cognitive and neuropathologic features of AD. In vitro studies show that Aβ can increase ion permeability in lipid membranes. This increased permeability is reportedly associated with the formation of artificial ion pores formed from Aβ oligomers. However, a number of other studies show that Aβ 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 Aβ and presenilin cause Ca2+ dysregulation in neurons will help to identify new drug targets for the treatment of AD.
