The nucleation growth and reversibility of Amyloid-beta deposition in vivo.
The amyloid-beta (Abeta) peptide is a major constituent of the brain senile plaques that characterize Alzheimer's disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Abeta deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Abeta deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Abeta-degrading enzyme, neprilysin, on aggregation and deposition of Abeta in apoE transgenic and control mice. The results revealed that Abeta deposition in vivo is initiated by aggregation of Abeta42, which is followed by reversible deposition of both Abeta42 and Abeta40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Abeta42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Abeta deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Abeta deposition was associated with increased gliosis, which may reflect early pathological interactions of beta with the brain's parenchyma.
Dolev
Iftach
I
The Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Michaelson
Daniel M
DM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3 / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002449:Cell Aggregation; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D016133:Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015260:Neprilysin