Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology

Amyloid beta protein (A betaP) is the major constituent of senile plaques a ssociated with Alzheimer's disease (AD). However, its mechanistic role in A D pathogenesis is poorly understood. Globular and nonfibrillar A beta Ps ar e continuously released during normal metabolism. Using techniques of atomi c force microscopy, laser confocal microscopy, electrical recording, and bi ochemical assays, we have examined the molecular conformations of reconstit uted globular A beta Ps as well as their real-time and acute effects on neu ritic degeneration. Atomic force microscopy (AFM) of A betaP(1-42) shows gl obular structures that do not form fibers in physiological-buffered solutio n for up to 8 h of continuous imaging. AFM of A betaP(1-42) reconstituted i n a planar lipid bilayer reveals multimeric channel-like structures. Consis tent with these AFM resolved channel-like structures, biochemical analysis demonstrates that predominantly monomeric A beta Ps in solution form stable tetramers and hexamers after incorporation into lipid membranes. Electroph ysiological recordings demonstrate the presence of multiple single channel currents of different sizes. At the cellular level, A betaP(1-42) allows ca lcium uptake and induces neuritic abnormality in a dose- and time-dependent fashion. At physiological nanomolar concentrations, rapid neuritic degener ation was observed within minutes; at micromolar concentrations, neuronal d eath was observed within 3-4 h. These effects are prevented by zinc (an A b etaP channel blocker) and by the removal of extracellular calcium, but are not prevented by antagonists of putative AbP cell surface receptors. Thus, A betaP channels may provide a direct pathway for calcium-dependent A betaP toxicity in AD.