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Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.
J Neurosci 2009; 29(25):7957-65JN

Abstract

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. A beta(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 A beta and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2(-/-) vaccinated mice, brain A beta 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.

Authors+Show Affiliations

Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. donna.wilcock@duke.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19553436

Citation

Wilcock, Donna M., et al. "Amyloid Reduction By Amyloid-beta Vaccination Also Reduces Mouse Tau Pathology and Protects From Neuron Loss in Two Mouse Models of Alzheimer's Disease." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 29, no. 25, 2009, pp. 7957-65.
Wilcock DM, Gharkholonarehe N, Van Nostrand WE, et al. Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. J Neurosci. 2009;29(25):7957-65.
Wilcock, D. M., Gharkholonarehe, N., Van Nostrand, W. E., Davis, J., Vitek, M. P., & Colton, C. A. (2009). Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 29(25), pp. 7957-65. doi:10.1523/JNEUROSCI.1339-09.2009.
Wilcock DM, et al. Amyloid Reduction By Amyloid-beta Vaccination Also Reduces Mouse Tau Pathology and Protects From Neuron Loss in Two Mouse Models of Alzheimer's Disease. J Neurosci. 2009 Jun 24;29(25):7957-65. PubMed PMID: 19553436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. AU - Wilcock,Donna M, AU - Gharkholonarehe,Nastaran, AU - Van Nostrand,William E, AU - Davis,Judianne, AU - Vitek,Michael P, AU - Colton,Carol A, PY - 2009/6/26/entrez PY - 2009/6/26/pubmed PY - 2009/8/6/medline SP - 7957 EP - 65 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 29 IS - 25 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. A beta(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 A beta and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2(-/-) vaccinated mice, brain A beta 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/19553436/Amyloid_reduction_by_amyloid_beta_vaccination_also_reduces_mouse_tau_pathology_and_protects_from_neuron_loss_in_two_mouse_models_of_Alzheimer's_disease_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=19553436 DB - PRIME DP - Unbound Medicine ER -