Possible role of tau in mediating pathological effects of apoE4 in vivo prior to and following activation of the amyloid cascade.
Injection of the neprilysin inhibitor thiorphan into the brain induces the accumulation of Abeta in hippocampal CA1 neurons and septal neurons in apoE4 knock-in mice but not in mice that express the corresponding Alzheimer's disease benign isoform apoE3. We investigated the possible role of tau phosphorylation in mediating this synergistic pathological cross talk between apoE4 and the amyloid cascade. This revealed that in both apoE4 and apoE3 mice, activating the amyloid cascade by inhibiting neprilysin triggers the accumulation of AT100 phosphorylated tau in the perikarya of CA1 neurons. In contrast, in the septum this treatment elevated the level of phosphorylation of the tau AT100 epitope only in the apoE4 mice. This suggests that tau-related processes by themselves do not mediate the synergistic pathological effects of apoE4 and Abeta in CA1 neurons. However, tau and cytoskeletal-related mechanisms may mediate the synergistic pathological effects of apoE4 and Abeta in the septum. The basal levels of tau phosphorylation are also affected by the apoE genotype. This effect, which is associated with hyperphosphorylation of the tau AT8 epitope, is most prominent in hippocampal CA3 neurons. This suggests that the apoE4 mice are already stressed under nonstimulated conditions and that AT8 tau phosphorylation may contribute to their increased susceptibility to brain insults.
Inbar
Dafna
D
Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Belinson
Haim
H
Rosenman
Hanna
H
Michaelson
Daniel M
DM
D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000008:administration & dosage; D020665:Septum of Brain / Q000166:cytology / Q000378:metabolism; D015244:Thiorphan / Q000008:administration & dosage; D016875:tau Proteins / Q000378:metabolism*
D000682:Amyloid; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D011480:Protease Inhibitors; D016875:tau Proteins; D015244:Thiorphan