p75NTR Regulates Aβ Deposition by Increasing Aβ Production But Inhibiting Aβ Aggregation with Its Extracellular Domain

Accumulation of toxic amyloid-beta (A beta) 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 A beta-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 A beta accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble A beta levels in the brain and serum, but increased the accumulation of insoluble A beta and A beta 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. A beta 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 A beta(42) peptide in vitro, and reduced local A beta 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 A beta levels by both increasing A beta production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.