Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity.
1. Alzheimer's disease (AD) is a chronic dementia and neurodegenerative 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 processing from a much larger amyloid precursor protein (APP), and has been circumstantially identified as the toxic principle causing cell damage in the disease. 4. The A beta P[1-40] peptide is able to form quite characteristic calcium channels in planar lipid bilayers. These channels 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 therapeutically useful in Alzheimer's Disease, and have constructed molecular models of the channels to aid in the design of such compounds.
Pollard
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HB
Laboratory of Cell Biology and Genetics, NIDDSK, National Institutes of Health, Bethesda, MD 20892, USA.
Arispe
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N
Rojas
E
E
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology* / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000502:physiology*; D008959:Models, Neurological; D008961:Models, Structural; D008969:Molecular Sequence Data; D009498:Neurotoxins; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007473:Ion Channels; D009498:Neurotoxins