TY - JOUR T1 - Amyloid Reduction by Amyloid-β Vaccination Also Reduces Mouse Tau Pathology and Protects from Neuron Loss in Two Mouse Models of Alzheimer's Disease JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7957 LP - 7965 DO - 10.1523/JNEUROSCI.1339-09.2009 VL - 29 IS - 25 AU - Donna M. Wilcock AU - Nastaran Gharkholonarehe AU - William E. Van Nostrand AU - Judianne Davis AU - Michael P. Vitek AU - Carol A. Colton Y1 - 2009/06/24 UR - http://www.jneurosci.org/content/29/25/7957.abstract N2 - 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, nonmutated 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%. 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 nonmutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD. ER -