Amyloid-β Peptides Stimulate the Expression of the p75 NTR Neurotrophin Receptor in SHSY5Y Human Neuroblastoma Cells and AD Transgenic Mice

Abstract

The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-β (Aβ)_1-42 oligomers that is accompanied by the downregulation of the Trk A neurotrophin receptor and by either upregulation or at least maintenance of the p75 neurotrophin receptor (p75^NTR), which can be stimulated by the accumulating Aβ_1-42 peptides. Here we show that Aβ_1-42 and its active fragment Aβ_25-35, but not Aβ_42-1, can at least double the level of p75^NTR receptors in the membranes of model SH-SY5Y human neuroblastoma cells. We also show that p75^NTR is upregulated in the hippocampi of two strains of AD transgenic mice. Specifically, the level of the p75^NTR receptor in the hippocampal membranes from 12–15 monthold AD-triple transgenic mice (3xTg-AD) harboring PS1_M146V, AβPP_Swe, and tau_P301L was nearly twice that in hippocampal membranes from age-matched wild-type mice. Similarly, the level of p75^NTR receptor in 7 month-old B6.Cg-Tg AD mice harboring PSEN1dE9 and AβPP_Swe was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Aβ_1-42 levels in the AD mice. Thus, it appears that it could be the accumulating Aβ_1-42 that increases or at least prevents the downregulation of p75^NTR receptors in key parts of AD brains. It is possible that when the Aβ_1-42 accumulation reaches a critical level in the brain on the way to late-onset AD, the Aβ_1-42-induced p75^NTR receptor signaling starts a vicious cycle that accelerates AD development because of the activated receptors' recently shown ability to stimulate Aβ_1-42 production.