Human Tau Gene Expression in a Transgenic Animal Model Altered by Developmental Pb Exposure

Abstract

Alzheimer’s Disease (AD), the sixth leading cause of death in the United States, is a neurodegenerative disease characterized by a decline in memory and cognitive function. Demographics show that more than 90% of patients are first diagnosed with AD after the age of 65, classified as Late Onset AD (LOAD). The remaining 10% are said to have Early Onset AD. Research has shown that no mutation is linked to LOAD. Thus we hypothesize that environmental and/or epigenetic factors may be playing a major role in LOAD. AD traits coincide with the presence of two pathological hallmarks found in the brain: amyloid-beta plaques and neurofibrillary tau tangles. The microtubule associated protein tau (MAPT) is primarily found in neuronal axons. A feature of AD is the hyperphosphorylation of tau, lowering its binding affinity to the microtubules and increasing the chance of toxic aggregates to entangle. This in vivo study uses a MAPT transgenic mouse model knocked out for murine tau and knocked in for the human tau gene. Lifespan protein profiles of total tau, phosphorylated tau (Ser396) and related kinases (CDK5) were compared to wild-type profiles to validate the genomic insertion of the transgene. The mouse model was then tested for the transgene’s ability to be altered by an environmental toxin. Pups were exposed to lead (Pb) from postnatal day (PND) 0-20 with 0.2% Pb acetate through the drinking water of the dam. Mice were sacrificed at PND 20, 30, 40, 50 and 60. Protein and mRNA levels of tau and CDK5 were investigated. Protein levels of Ser396 were also measured. DNMT1 protein levels were measured to evaluate the ability of Pb to affect epigenetic regulators in this mouse model. We can conclude that this human tau transgene has been genomically inserted in a similar location to the endogenous murine tau gene. The human tau transgene is also able to be manipulated by environmental exposures, such as the heavy metal Pb, making this mouse line a good model to use for future AD studies. Our findings are the first of their kind to test the responsiveness of the human tau gene to an environmental toxin, specifically lead (Pb).