p75NTR regulates A{Beta} deposition by increasing A{Beta} production but inhibiting A{Beta} aggregation with its extracellular domain

Yan-Jiang Wang, Xin Wang, Jianjun Lu, Qiao-Xin Li, Chang Gao, Xiao-Hong Liu, Ying Sun, Miao Yang, Yoon Lim, Genevieve Evin, Jin-Hua Zhong, Colin Masters, Xin-Fu Zhou

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    Abstract

    Accumulation of toxic amyloid-β(Aβ) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer's disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Aβ-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII-/- mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Aβ accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Aβ levels in the brain and serum, but increased the accumulation of insoluble Aβ and Aβ plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or α-, β-, and γ-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Aβ production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR gene in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Aβ 42 peptide in vitro, and reduced local Aβ plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Aβ levels by both increasing Aβ production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.

    Original languageEnglish
    Pages (from-to)2292-2304
    Number of pages13
    JournalJournal of Neuroscience
    Volume31
    Issue number(6)
    DOIs
    Publication statusPublished - 2011

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    Wang, Y-J., Wang, X., Lu, J., Li, Q-X., Gao, C., Liu, X-H., Sun, Y., Yang, M., Lim, Y., Evin, G., Zhong, J-H., Masters, C., & Zhou, X-F. (2011). p75NTR regulates A{Beta} deposition by increasing A{Beta} production but inhibiting A{Beta} aggregation with its extracellular domain. Journal of Neuroscience, 31((6)), 2292-2304. https://doi.org/10.1523/JNEUROSCI.2733-10.2011