Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.
Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.
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DOI：
10.1523/jneurosci.1339-09.2009
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发表时间：
2009-06-24
期刊：
影响因子：
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通讯作者：
Colton CA
中科院分区：
文献类型：
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作者：
Wilcock DM;Gharkholonarehe N;Van Nostrand WE;Davis J;Vitek MP;Colton CA
Shown to lower amyloid deposits and improve cognition in APP transgenic mouse models, immunotherapy appears to be a promising approach for the treatment of Alzheimer’s disease (AD). Due to limitations in available animal models, however, it has been unclear whether targeting amyloid is sufficient to reduce the other pathological hallmarks of AD—namely, accumulation of pathological, non-mutated tau and neuronal loss. We have now developed two transgenic mouse models (APPSw/NOS2−/− and APPSwDI/NOS2−/−) that more closely model AD. These mice show amyloid pathology, hyperphosphorylated and aggregated normal mouse tau, significant neuron loss, and cognitive deficits. Aβ1–42 or KLH vaccinations were started in these animals at 12 months, when disease progression and cognitive decline are well underway, and continued for 4 months. Vaccinated APPSwDI/NOS2−/− mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain Aβ and a 35–45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2−/− vaccinated mice, brain Aβ was reduced by 65–85% and hyperphosphorylated tau by 50–60 percent. Furthermore, neurons were completely protected, and memory deficits were fully reversed. Microhemorrhage was observed in all vaccinated APPSw/NOS2−/− mice and remains a significant adverse event associated with immunotherapy. Nevertheless, by providing evidence that reducing amyloid pathology also reduces non-mutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD.
