A nontransgenic mouse model shows inducible amyloid-beta (Abeta) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade.
The amyloid-beta (Abeta) peptide, a major pathological hallmark of Alzheimer's disease (AD), undergoes a cascade of interactions resulting in the formation of soluble aggregates and their conversion in the brain to insoluble deposits and mature senile plaques. Furthermore, the apoE4 isoform of apolipoprotein E (apoE), which is the major genetic risk factor of AD, is associated with increased Abeta deposition. It is not known how the different Abeta aggregates in the amyloid cascade are formed, contribute to the pathogenesis of AD, or are affected by apoE4. To investigate the initial aggregation stages underlying the amyloid cascade in vivo and how apoE affects them, we examined the effects of prolonged inhibition and subsequent reactivation of the Abeta-degrading protease neprilysin on deposition, disaggregation, and fibrillization of Abeta in apoE-transgenic and control mice. In control mice, intracerebroventricular infusion of thiorphan, which inhibits neprilysin, induced Abeta42 and Abeta40 deposition and fibrillization. On termination of thiorphan treatment, the number of Abeta deposits decreased, whereas the fibrillar Abeta deposits were unaffected. Similar treatments in apoE-deficient mice and mice transgenic for human apoE4 or apoE3 revealed that apoE4 enhances specifically the nucleation and aggregation of immunopositive Abeta deposits and that reversible disaggregation of these deposits and their irreversible conversion to fibrillar deposits are stimulated similarly by the different apoE isoforms. Deposition of Abeta and its enhancement by apoE4 were accompanied by increased astrogliosis both far from and near the Abeta deposits, suggesting that astrogliosis might be triggered by both insoluble and soluble Abeta aggregates.
Dolev
Iftach
I
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Michaelson
Daniel M
DM
D000544:Alzheimer Disease / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
D000682:Amyloid; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E