Abstract
Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer’s disease, is histopathologically associated with increased deposition of amyloid-β 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 Aβ-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 Aβ in the affected neurons. We presently examined the extent to which this apoE4-dependent Aβ-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 Aβ in CA1 neurons. In contrast, the corresponding apoE4-dependent Aβ 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.
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Acknowledgments
This work was supported in part by grants from the Israel Science Foundation (ISF grant # 487/07), and from the Joseph and Inez Eichenbaum Foundation, and by the LIPIDIDIET grant funded by the seventh Framework Programme of the European Union. DMM is the incumbent of the Myriam Lebaoh Chair in Molecular Neurodegeneration.
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Dedicated to the special issue of the JERUSALEM meeting.
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Belinson, H., Michaelson, D.M. ApoE4-dependent Aβ-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum. J Neural Transm 116, 1427–1434 (2009). https://doi.org/10.1007/s00702-009-0218-9
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DOI: https://doi.org/10.1007/s00702-009-0218-9