Southampton General Hospital, University of Southampton, UK.
Acta Neuropathol. 2010 Jul;120(1):13-20. doi: 10.1007/s00401-010-0705-y. Epub 2010 Jun 9.
Alzheimer's disease (AD) pathology is characterised by aggregation in the brain of amyloid-beta (Abeta) peptide and hyperphosphorylated tau (phospho-tau), although how these proteins interact in disease pathogenesis is unclear. Abeta immunisation results in removal of Abeta from the brain but cognitive decline continues to progress, possibly due to persistent phospho-tau. We quantified phospho-tau and Abeta42 in the brains of 10 AD patients (iAD) who were actively immunised with Abeta42 (AN1792, Elan Pharmaceuticals) compared with 28 unimmunised AD cases (cAD). The phospho-tau load was lower in the iAD than the cAD group in the cerebral cortex (cAD 1.08% vs. iAD 0.72%, P = 0.048), CA1 hippocampus (cAD 2.26% vs. iAD 1.05%; P = 0.001), subiculum (cAD 1.60% vs. iAD 0.31%; P = 0.001) and entorhinal cortex (cAD 1.10% vs. iAD 0.18%; P < 0.001). Assessment of the localisation within neurons of phospho-tau indicated that the Abeta immunotherapy-associated reduction was confined to neuronal processes, i.e. neuropil threads and dystrophic neurites. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected. In showing that Abeta immunisation can influence phospho-tau pathology, we confirm the position of Abeta as a target for modifying tau accumulation in AD and demonstrate a link between these proteins. However, the continuing progression of cognitive decline in AD patients after Abeta immunisation may be explained by its lack of apparent effect on tangles.
阿尔茨海默病（AD）的病理学特征是淀粉样β（Abeta）肽和过度磷酸化的 tau（磷酸化 tau）在大脑中的聚集，尽管这些蛋白质在疾病发病机制中的相互作用尚不清楚。Abeta 免疫接种可导致 Abeta 从大脑中清除，但认知能力下降仍在继续进展，这可能是由于磷酸化 tau 的持续存在。我们对 10 名接受 Abeta42（AN1792，Elan 制药公司）主动免疫接种的 AD 患者（iAD）和 28 名未免疫接种的 AD 患者（cAD）的大脑中的磷酸化 tau 和 Abeta42 进行了定量分析。与 cAD 组相比，iAD 组大脑皮质（cAD 为 1.08%，iAD 为 0.72%，P=0.048）、CA1 海马区（cAD 为 2.26%，iAD 为 1.05%；P=0.001）、下托区（cAD 为 1.60%，iAD 为 0.31%；P=0.001）和内嗅皮层（cAD 为 1.10%，iAD 为 0.18%；P<0.001）中的磷酸化 tau 负荷较低。对磷酸化 tau 在神经元内的定位评估表明，Abeta 免疫治疗相关的减少仅限于神经元过程，即神经突丝和营养不良的神经突。然而，似乎不会影响导致神经原纤维缠结的神经元胞体中的磷酸化 tau 积累。通过证明 Abeta 免疫接种可以影响磷酸化 tau 病理学，我们证实了 Abeta 作为改变 AD 中 tau 积累的靶标，并且证实了这两种蛋白质之间存在联系。然而，AD 患者在 Abeta 免疫接种后认知能力下降仍在继续进展，这可能是由于其对缠结的影响不明显。
