ION-CHANNEL HYPOTHESIS FOR ALZHEIMER AMYLOID PEPTIDE NEUROTOXICITY

1. Alzheimer's disease (AD) is a chronic dementia and neurodegenerativ e disorder affecting the oldest portions of the population, Brains of AD patients accumulate large amount of the A beta P peptide in amyloid plaques. 2. The A beta P[1-40] peptide is derived by proteolytic proc essing from a much larger amyloid precursor protein (APP), and has bee n circumstantially identified as the toxic principle causing cell dama ge in the disease. 4. The A beta P[1-40] peptide is able to form quite characteristic calcium channels in planar lipid bilayers, These chann els have conductances in the nS range, and can dissipate ion gradients quickly, The peptide can also cause equivalent cation conductances in cells. 5. We suggest that amyloid channel blocking agents might be th erapeutically useful in Alzheimer's Disease, and have constructed mole cular models of the channels to aid in the design of such compounds.