O2–04–02: Cognitive and pathological effects of regulatable tau in adult mice

Neurofibrillary tangles (NFTs) are associated with cognitive decline and neuron loss in Alzheimer's disease (AD). It has recently been shown that transgenic mice over–expressing a regulatable human tau mutation (P301L) from birth develop NFTs, neuronal loss and memory deficits, as a function of age. When tau over–expression is subsequently suppressed, memory function recovers but NFTs continue to accrue, suggesting phosphorylated tau itself, not NFTs alone, may be responsible for cognitive deficits in this model. 1. Assess behavior and brain pathology as it relates to over–expression of mutant human tau in a regulatable transgenic model of tauopathy. 2. Determine if suppression of mutant tau over–expression reverses cognitive deficits. We began tau suppression in utero and continued to suppress the mutant protein until 6.5 months of age, at which time we allowed mutant tau to over–express. From 3 months until the end of the study, mice were assessed under the Fixed Consecutive Number (FCN) assay which requires the animal to complete a fixed number of responses (5 or more) on the “work” lever before switching to the “reward” lever to receive food. This test assesses reference memory for the “rules” of the contingency relationship between lever choice, pressing and reward, as well as gauges the strength of the learned conditional discrimination associated with interoceptive feedback from pressing behavior and accurate switching. When tau is suppressed in utero through adulthood in this model, no discernable cognitive deficits developed through 6.5 months of age. No motor or motivational deficits were observed. After 6.5 months of age, we kept mutant tau suppressed in half the transgenic mice but allowed tau to over–express in six mice for 2.5 months, until they were 9 months of age. No significant cognitive impairments were found under FCN after 2.5 months of mutant tau over expression in this group of adult mice. Prenatal suppression of tau prevents cognitive and motor deficits well into adulthood in this model. Rescue of cognition may occur if tau is suppressed after deficits develop. Mutant mice continue under both suppression and over–expression of tau in this ongoing study.