| First Author | Wang YJ | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 6 | Pages | 2292-304 |
| PubMed ID | 21307265 | Mgi Jnum | J:169451 |
| Mgi Id | MGI:4941066 | Doi | 10.1523/JNEUROSCI.2733-10.2011 |
| Citation | Wang YJ, et al. (2011) p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci 31(6):2292-304 |
| abstractText | Accumulation of toxic amyloid-beta (Abeta) 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 Abeta-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 Abeta accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Abeta levels in the brain and serum, but increased the accumulation of insoluble Abeta and Abeta plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or alpha-, beta-, and gamma-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Abeta 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 Abeta(42) peptide in vitro, and reduced local Abeta 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 Abeta levels by both increasing Abeta production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology. |
