Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wilcock, DM; Gharkholonarehe, N; Van Nostrand, WE; Davis, J; Vitek, MP; Colton, CA

Published Date

  • June 24, 2009

Published In

Volume / Issue

  • 29 / 25

Start / End Page

  • 7957 - 7965

PubMed ID

  • 19553436

Pubmed Central ID

  • PMC2871319

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.1339-09.2009


  • eng

Conference Location

  • United States