Abstract
The greatest risk factor for developing Alzheimer’s disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human tau transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals.
Highlights
Tauopathies are a group of neurodegenerative disorders involving the tau protein.Alzheimer’s disease (AD), the most common tauopathy, affects 5.4 million Americans and accounts for 60 to 80 percent of all dementia cases [1]
Though we have previously shown this “leakage” to be insufficient to produce memory deficits in young P301L mice [11], it is possible this low-level tau expression may eventually result in increased total tau in older mice on DOX for a longer period of time
Chronic suppression of the tTA system with DOX has been shown to result in less protein expression when DOX is withdrawn, though this effect is observed when DOX is delivered at 200 ppm
Summary
Tauopathies are a group of neurodegenerative disorders involving the tau protein.Alzheimer’s disease (AD), the most common tauopathy, affects 5.4 million Americans and accounts for 60 to 80 percent of all dementia cases [1]. Tauopathies are a group of neurodegenerative disorders involving the tau protein. While an overwhelming majority of animal research has focused on aberrant processing of Aβ as the initiating event for AD pathology, and for good reason [4,5], clinical drug trials targeting Aβ have been largely unsuccessful [6,7,8]. This obstacle necessitates parallel lines of research, including those focused on abnormalities in the tau protein and the downstream alterations produced by tau
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