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The Journal of Neuroscience, June 24, 2009, 29(25):7957-7965; doi:10.1523/JNEUROSCI.1339-09.2009

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Neurobiology of Disease
Amyloid Reduction by Amyloid-β Vaccination Also Reduces Mouse Tau Pathology and Protects from Neuron Loss in Two Mouse Models of Alzheimer's Disease

Donna M. Wilcock,¹ Nastaran Gharkholonarehe,¹ William E. Van Nostrand,² Judianne Davis,² Michael P. Vitek,¹ and Carol A. Colton¹

¹Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, and ²Department of Medicine, Stony Brook University, Stony Brook, New York 11794

Correspondence should be addressed to Donna M. Wilcock, Division of Neurology, Department of Medicine, Duke University Medical Center, Bryan Research Building, Box 2900, Research Drive, Durham, NC 27710. Email: donna.wilcock{at}duke.edu

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. Aβ_1–42 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.

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Received March 19, 2009; revised May 7, 2009; accepted May 11, 2009.

Correspondence should be addressed to Donna M. Wilcock, Division of Neurology, Department of Medicine, Duke University Medical Center, Bryan Research Building, Box 2900, Research Drive, Durham, NC 27710. Email: donna.wilcock{at}duke.edu

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