Transgenic mouse models for Alzheimer's disease:: the role of GSK-3β in combined amyloid and tau-pathology

Describing and understanding the pathological processes which devastate the brain of Alzheimer's disease (AD) patients remains a major target for experimental biology. We approached this problem by generating different types of single and double transgenic mice that develop pathological hallmarks of AD. In APP-V717 mice, the progression from intracellular amyloid to diffuse and senile plaques with vascular deposits; is preceded by early defects in cognition and LTP. In Tau-P301L mice, the morbid tauopathy with intracellular filaments, cause mortality before age 1 year. Ageing APP-V717lxTau-P301L double tg mice (14-17 months) have combined AD-like pathology in hippocampus and cortex consisting of amyloid plaques and neurofibrillary tangles. Remarkably, while Tau-P301L mice die before age 1 year, the APP-V7171xTau-P301L double tg mice survive much longer, which correlates with alleviation of tauopathy in hindbrain, despite aggravation in forebrain. This hypothesis is corroborated in Tau-P301 LxGSK-3 beta double transgenic mice, which have also an extended lifespan relative to Tau-P301L mice, that correlates with reduction of brainstem tauopathy. At the same time, Tau-P301LxGSK-3 beta mice have dramatic forebrain tauopathy, with tangles in almost all neurons, although without hyper-phosphorylation of Tau. The data corroborate the hypothesis that GSK-3 beta is the missing link between the amyloid and tau-pathology, and position GSK-3 beta as prominent player in the pathogenesis in AD.