Channel Formation by a Neurotoxic Beta Amyloid Peptide, Aβ25–35

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder which is accompanied by memory loss and defects in cognitive function. The features in AD brains include extracellular senile plaques, intracellular neurofibrillary tangles, and amyloid proteins deposited in walls of cerebral and meningeal blood vessels. The major component of these pathognomonic lesions of AD has been identified as a 39–43 amino acid long peptide called beta amyloid peptide (Aβ). Aβ is derived from the amyloid β precursor protein (βAPP)¹. The thesis that Aβ deposition plays a central role in the pathogenesis of AD has garnered increasing attention. It has been demonstrated that Aβ either is directly neurotoxic to neurons in culture,^2,3 or potentiates neuronal vulnerability to excitatory neurotoxins.^4,5 Neurotoxic activity has been reported to be located in the fragment of Aβ, Aβ25–35.² We hypothesize that Aβ and its fragments, such as Aβ25–35, can form ion channels in neuronal membrane, which may allow calcium entry either directly or indirectly, thus leading to neuronal death and neuropathology of AD. In this study, we will characterize the ionic channels formed by Aβ25–35. Preliminary reports of this work have appeared elsewhere.^6,7,8