An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease.
Alzheimer's disease is a complex neurodegenerative process that is believed to be due to the accumulation of short, hydrophobic peptides derived from amyloid precursor proteins by proteolytic cleavage. It is widely believed that these Abeta peptides are secreted into the extracellular spaces of the CNS, where they assemble into toxic oligomers that kill neurons and eventually form deposits of senile plaques. This essay explores the possibility that a fraction of these Abeta peptides never leave the membrane lipid bilayer after they are generated, but instead exert their toxic effects by competing with and compromising the functions of intramembranous segments of membrane-bound proteins that serve many critical functions. Based on the presence of shared amino acid sequences containing GxxG motifs, I speculate that accumulations of intramembranous Abeta peptides might affect the functions of amyloid precursor protein itself and the assembly of the PS1, Aph1, Pen 2, Nicastrin complex.
Marchesi
Vincent T
VT
Department of Pathology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA. vincent.marchesi@yale.edu
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System; D019281:Dimerization; D010450:Endopeptidases; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010447:Peptide Hydrolases; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013696:Temperature
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C469349:PSENEN protein, human; D010455:Peptides; D053764:Presenilin-1; C413604:nicastrin protein; D012967:Sodium Dodecyl Sulfate; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases