The allele E4 of
apolipoprotein E (
apoE4), the most prevalent genetic risk factor for
Alzheimer's disease, is associated histopathologically with elevated levels of brain
amyloid. This led to the suggestion that the pathological effects of
apoE4 are mediated by cross-talk interactions with
amyloid beta peptide (Abeta), which accentuate the pathological effects of the
amyloid cascade. The mechanisms underlying the Abeta-mediated pathological effects of
apoE4 are unknown. We have shown recently that inhibition of the Abeta-degrading
enzyme neprilysin in brains of wild-type
apoE3 and
apoE4 mice results in rapid and similar elevations in their total brain Abeta levels. However, the nucleation and aggregation of Abeta in these mice were markedly affected by the
apoE genotype and were specifically enhanced in the
apoE4 mice. We presently used the
neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by
apoE4 after activation of the
amyloid cascade. This revealed that
apoE4 stimulates
isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Abeta and
apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated
isoform specifically with the occurrence of pronounced cognitive deficits in the
ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between
apoE4 and Abeta, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the
amyloid cascade and the effects thereon of
apoE4.