The amyloid beta ion channel hypothesis of Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of chronic dementia in the US. Its incidence is increasing with an attendant increase in associated health care costs. Since its first description in a patient by Dr. Alois Alzheimer over a century ago, a large body of biomedical literature has established a detailed clinical and molecular profile of this disorder. Amyloid beta peptide (Abeta; a 39-42 amino acid molecule) is the major component of senile plaques, the lesions that are one of the pathologic hallmarks of AD (Wong et al 1985). Although many aspects of the biology of amyloid beta have been investigated, several fundamental questions about how this peptide causes AD neuropathology remain unanswered. The key question is: How is Abeta toxic to cerebral neurons? Because plaques are extra-neuronal deposits, it is difficult to imagine a structural basis for their toxicity. As an interesting contrast the other pathognomonic feature of AD, neurofibrillary tangles, are intra-axonal structural anomalies that are composed of the hyperphosphorylated microtubule associated (MAP) protein, tau. This review will assess the current thinking that relates to a recent hypothesis of Abeta toxicity. In 1992, Hardy and Higgins reported findings that suggested a new and intriguing possibility. These authors found that Abeta peptides disrupt Ca(2+) homeostasis in neurons and increase intracellular Ca(2+) [Ca(2+)](i). This was corroborated by Mattson and his colleagues who demonstrated that Abeta exposure to human cortical neurons raised [Ca2(+)](i) (Mattson, Cheng et al 1992); (Hardy and Higgins 1992). Finally, Nelson Arispe's group at the NIH specifically investigated the possibility that Abeta peptides might function like Ca(2+) ion channels (Arispe et al 1993). This and several subsequent studies have laid the foundation for a novel idea: "Abeta peptides are, in part, toxic to neurons because they form aberrant ion channels in neuronal membranes and thereby disrupt neuronal homeostasis". In this review we shall critically examine this theory in light of classic and contemporary literature.