Alzheimer A beta amyloid forms an inhibitory neuronal substrate.
Alzheimer's disease (AD) is identified by the accumulation of amyloid plaques, neurofibrillary degeneration, and the accompanying neuronal loss. AD amyloid assembles into compact fibrous deposits from the amyloid beta (A beta) protein, which is a proteolytic fragment of the membrane-associated amyloid precursor protein. To examine the effects of amyloid on neuron growth, a hybrid mouse motoneuron cell line (NSC34) exhibiting spontaneous process formation was exposed to artificial "plaques" created from aggregated synthetic A beta peptides. These correspond to full-length A beta residues 1-40 (A beta 1-40), an internal beta-sheet region comprising residues 11-28 (A beta 11-28), and a proposed toxic fragment comprising residues 25-35 (A beta 25-35). Fibers were immobilized onto culture dishes, and addition of cells to these in vitro plaques revealed that A beta was not a permissive substrate for cell adhesion. Neurites in close contact with these deposits displayed abnormal swelling and a tendency to avoid contact with the A beta fibers. In contrast, A beta did not affect the adhesion or growth of rat astrocytes, implicating a specific A beta-neuron relationship. The inhibitory effects were also unique to A beta as no response was observed to deposits of pancreatic islet amyloid polypeptide fibers. Considering the importance of cell adhesion in neurite elongation and axonal guidance, the antiadhesive properties of A beta amyloid plaques found in vivo may contribute to the neuronal loss responsible for the clinical manifestations of AD.
Fraser
P E
PE
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada.
Lévesque
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L
McLachlan
D R
DR
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D006822:Hybrid Cells; D058228:Islet Amyloid Polypeptide; D051379:Mice; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide