title: p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain.
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.
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide 5001, South Australia, Australia. yanjiang_wang@tmmu.edu.cn
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Lu
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.forename: Chang-Yue
authors.initials: CY
authors.lastname: Gao
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Liu
authors.forename: Yin
authors.initials: Y
authors.lastname: Sun
authors.forename: Miao
authors.initials: M
authors.lastname: Yang
authors.forename: Yoon
authors.initials: Y
authors.lastname: Lim
authors.forename: Genevieve
authors.initials: G
authors.lastname: Evin
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Zhong
authors.forename: Colin
authors.initials: C
authors.lastname: Masters
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
mesh_terms: D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007339:Insulysin / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015260:Neprilysin / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D015260:Neprilysin; D007339:Insulysin