Critical questions regarding the mechanisms of protein pathology and synapse loss in Alzheimer disease (AD) remain unanswered. A2 and tau, the primary proteins implicated in Alzheimer disease pathology, are known to accumulate and form insoluble plaques and tangles, respectively. However, the relationship between the toxic, soluble intermediates of these proteins, particularly in the synapse, is poorly understood. Elucidating these pathways will provide us with novel targets for AD therapeutics. Here, multiple transgenic mice will be created to study the effects of A2 on wild-type tau pathology in vivo, and the contributions of each pathology type to synaptic dysfunction and cognitive decline. Two single lines have already been created, hAPPSLloxP, which produces robust A2 pathology, and hTau, which overexpresses wild type human full- length tau. These lines will be crossed to form a novel double transgenic model of AD, and all three lines will be compared to assess A2 -dependent and independent effects on cognition and pathology. Additionally, the loxP sites will be utilized to eliminate the APP transgene at three different pathological time points in the double transgenic mice. The cognitive effects and tau pathology resulting after APP suppression will provide proof of concept as to whether a perfect A2 therapy will be successful in treating AD, depending on the state of disease progression in the individual. Additionally, the downstream effects of APP suppression maybe provide new targets for therapeutic intervention. Furthermore, a precise study on what form of A2 specifically facilitates tau pathology will be performed in the single transgenic hTau mice. Two lines of somatic brain transgenics will be created using different viral constructs: one that will produce A2 intracellularly, and another which will produce A2 and transport it extracellularly. After a behavior assessment, these animals will be analyzed for A2 and tau pathology, localization, and correlations of pathology with cognition. The sum of these experiments will provide the field with a large amount of evidence as to how A2 and tau interact, which factors lead to neurodegeneration, and what must be targeted to stop the downward spiral of memory loss in AD.
Alzheimer disease (AD) is the most prevalent neurodegenerative disorder, with over 35 million people throughout the world suffering from the disease. If preventative treatment is not found quickly, every family will know someone who is afflicted with AD, as prevalence is expected to increase by more than 50% by the year 2030 (Hebert 2003). Pathologically, AD is defined by amyloid-beta (A2) plaques, neurofibrillary tangles, widespread synaptic loss, and neuronal death. It is imperative to understand the mechanisms that link A2, tau and cognitive decline in order to effectively treat the disease.
|Chabrier, Meredith A; Cheng, David; Castello, Nicholas A et al. (2014) Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease. Neurobiol Dis 64:107-17|
|Chabrier, Meredith A; Blurton-Jones, Mathew; Agazaryan, Andranik A et al. (2012) Soluble aÃ½Ã½ promotes wild-type tau pathology in vivo. J Neurosci 32:17345-50|