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

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/NOS2Ϫ/Ϫ 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␤ 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 Ϫ/Ϫ mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain A␤ and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2 Ϫ/Ϫ vaccinated mice, brain A␤ 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 Ϫ/Ϫ 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.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…The effects on tau seen in the 2xTg mouse can be recapitulated by direct Aβ fibril injection, implying that Aβ is the minimal fragment of APP required to transform tau [52]. Similarly, Aβ vaccination reduces both Aβ and tau pathology and protects against neuron loss [53][54][55].…”

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

“…A/T mice thus offer the opportunity to test whether strategies that can reverse or attenuate excessive matrix protein accumulation and vascular stiffness will diminish CAA. Used in conjunction with A␤ immunotherapy, these could help counter the transient increase in CAA and risk of cerebral microhemorrhages reported with vaccination in AD models 36 and human trials. 37 In addition, attenuating CAA could improve the function of astrocytes, key intermediaries in neurovascular coupling.…”

Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies

“…Thus, all these findings suggest that Aβ has the central role in the pathological mechanism of AD (Tabira, 2004). Indeed, reduction of Aβ pathology by vaccination induced reduction of tau pathology (Wilcock et al 2009). …”