National Research Council Canada, Institute for Biological Sciences, Ottawa, ON, Canada.
J Alzheimers Dis. 2010;19(3):915-25. doi: 10.3233/JAD-2010-1288.
The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-beta (Abeta)(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 Abeta(1-42) peptides. Here we show that Abeta(1-42) and its active fragment Abeta(25-35), but not Abeta(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 month old AD-triple transgenic mice (3xTg-AD) harboring PS1 (M146V), AbetaPP (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 AbetaPP (Swe) was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Abeta(1-42) levels in the AD mice. Thus, it appears that it could be the accumulating Abeta(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 Abeta (1-42) accumulation reaches a critical level in the brain on the way to late-onset AD, the Abeta (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 Abeta(1-42) production.
阿尔茨海默病（AD）晚期的进展是由淀粉样β（Abeta）（1-42）寡聚体的积累驱动的，伴随着 Trk A 神经营养因子受体的下调，以及 p75 神经营养因子受体（p75（NTR））的上调或至少维持，p75（NTR）受体可被积累的 Abeta（1-42）肽刺激。在这里，我们发现 Abeta（1-42）及其活性片段 Abeta（25-35），但不是 Abeta（42-1），至少可以使模型 SH-SY5Y 人神经母细胞瘤细胞膜中的 p75（NTR）受体水平增加一倍。我们还发现 p75（NTR）在两种 AD 转基因小鼠的海马中上调。具体来说，在携带 PS1（M146V）、AbetaPP（Swe）和 tau（P301L）的 12-15 个月大的 AD 三转基因小鼠（3xTg-AD）的海马膜中的 p75（NTR）受体水平几乎是年龄匹配的野生型小鼠的两倍。同样，在携带 PSEN1dE9 和 AbetaPP（Swe）的 7 个月大的 B6.Cg-Tg AD 小鼠中，p75（NTR）受体的水平也高于相应的野生型小鼠。这种增加与 AD 小鼠中 Abeta（1-42）水平的年龄依赖性升高相关。因此，似乎是积累的 Abeta（1-42）增加或至少防止了 AD 大脑关键部位 p75（NTR）受体的下调。当 Abeta（1-42）在向晚发性 AD 发展的过程中在大脑中积累到临界水平时，Abeta（1-42）诱导的 p75（NTR）受体信号可能开始一个恶性循环，因为最近发现激活的受体能够刺激 Abeta（1-42）的产生，从而加速 AD 的发展。
