ApoE4-dependent Abeta-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum.
Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease, is histopathologically associated with increased deposition of amyloid-beta and brain inflammation and with impaired neuronal plasticity and repair. We have recently shown that the activation of the amyloid cascade by inhibition of the Abeta-degrading enzyme, neprilysin, stimulates the isoform-specific degeneration of hippocampal CA1 neurons and septal neurons in apoE4 transgenic mice and that this effect is accompanied by the accumulation of intracellular Abeta in the affected neurons. We presently examined the extent to which this apoE4-dependent Abeta-mediated neurodegeneration is associated with brain area specific inflammatory activation. This revealed that the activation of the amyloid cascade in apoE transgenic mice results in the activation of microgliosis and astrogliosis in the hippocampus of apoE4, but not in apoE3 transgenic mice. The effect was most pronounced in the hippocampal CA1 subfield and its initial kinetics followed that of the accumulation of Abeta in CA1 neurons. In contrast, the corresponding apoE4-dependent Abeta degeneration of septal neurons was not associated with the activation of either gliosis or astrogliosis in this brain area. These animal model findings, that the association between brain inflammation and neurodegeneration is brain area specific, suggest that neuropathological inflammatory interactions in AD may also be brain area specific and that consequently the efficacy of putative anti-inflammatory intervention may also be brain area selective.
The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Haim
H
Belinson
Daniel M
DM
Michaelson
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012686:Septal Nuclei / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015260:Neprilysin