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Neuroscience Research Institute, University of California, Santa Barbara, California 93016, USA
2Correspondence: Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA. E-mail: lal{at}lifesci.ucsb.edu
Amyloid ß protein (AßP) is the major constituent of senile plaques associated with Alzheimer’s disease (AD). However, its mechanistic role in AD pathogenesis is poorly understood. Globular and nonfibrillar AßPs are continuously released during normal metabolism. Using techniques of atomic force microscopy, laser confocal microscopy, electrical recording, and biochemical assays, we have examined the molecular conformations of reconstituted globular AßPs as well as their real-time and acute effects on neuritic degeneration. Atomic force microscopy (AFM) of AßP1–42 shows globular structures that do not form fibers in physiological-buffered solution for up to 8 h of continuous imaging. AFM of AßP1–42 reconstituted in a planar lipid bilayer reveals multimeric channel-like structures. Consistent with these AFM resolved channel-like structures, biochemical analysis demonstrates that predominantly monomeric AßPs in solution form stable tetramers and hexamers after incorporation into lipid membranes. Electrophysiological recordings demonstrate the presence of multiple single channel currents of different sizes. At the cellular level, AßP1–42 allows calcium uptake and induces neuritic abnormality in a dose- and time-dependent fashion. At physiological nanomolar concentrations, rapid neuritic degeneration was observed within minutes; at micromolar concentrations, neuronal death was observed within 3–4 h. These effects are prevented by zinc (an AßP channel blocker) and by the removal of extracellular calcium, but are not prevented by antagonists of putative AßP cell surface receptors. Thus, AßP channels may provide a direct pathway for calcium-dependent AßP toxicity in AD.—Lin, H., Bhatia, R., Lal, R. Amyloid ß-protein forms ion channels: implications for Alzheimer’s disease pathophysiology.
Key Words: atomic force microscope • AßP • calcium uptake • AD
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