Past events

The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer’s disease, is associated with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated via synergistic pathological interactions with amyloid β (Aβ). We have recently shown that activation of the amyloid cascade by inhibition of the Aβ-degrading enzyme neprilysin in brains of apoE3 and apoE4 mice results in the isoform specific degeneration in apoE4 mice, of hippocampal CA1 neurons and of entorhinal and septal neurons. This is accompanied by the accumulation of intracellular Aβ and apoE and by pronounced cognitive deficits in the ApoE4 mice. We presently investigated the cellular mechanisms underlying the apoE4 dependent Aβ mediated neurodegeneration of CA1 and septal neurons and their neuronal specificity. Confocal microscopy kinetic studies revealed that the accumulated Aβ in CA1 neurons of apoE4 mice co-localizes with lysosomes and is associated with lysosomal activation and subsequent apoptotic neuronal cell death. Furthermore the accumulated Aβ is oligomerized. In contrast the degeneration of septal neurons is not associated with oligomerization of the accumulated Aβ. Instead intracellular Aβ in septal neurons co-localizes with the apoE receptor LRP whose levels are specifically elevated in these cells. These findings suggest that the apoE4 dependent Aβ mediated neurodegeneration is related, in CA1 but not in septal neurons, to oligomerization of the accumulated Aβ. In addition, neurodegeneration of CA1 but not of septal neurons is associated with inflammatory activation suggesting that the brain area specificity of the effects of apoE4 and Aβ are also related to brain area specific non neuronal mechanisms such as inflammation. Neuronal plasticity experiments revealed that apoE4 inhibits synaptogenesis and neurogenesis and stimulates apoptosis in hippocampal neurons of apoE4 mice that have been exposed to an enriched environment. These effects are also associated with the specific accumulation of apoE4 and oligomerized Aβ in the affected neurons. Additional experiments revealed that apoE4 up-regulates the expression of inflammation-related genes following i.c.v injection of LPS and that this effect is also associated with the accumulation of intra neuronal Aβ in hippocampal neurons. These findings suggest that the impaired neuronal plasticity and hyper inflammatory effects of apoE4 may also be mediated via cross talk interactions of apoE4 with the amyloid cascade.