The longitudinal effects of pseudophosphorylated human tau on locus coeruleus fibre density in temporal lobe structures and its behavioural consequences in male and female rats

Wasef, Marie Ann (2021) The longitudinal effects of pseudophosphorylated human tau on locus coeruleus fibre density in temporal lobe structures and its behavioural consequences in male and female rats. Masters thesis, Memorial University of Newfoundland.

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Abstract

Abnormally phosphorylated tau is a protein commonly associated with Alzheimer disease (AD). Braak and Del Tredici (2011) have identified a noradrenergic nucleus, the locus coeruleus (LC), as the brain region to first express abnormal tau. Using a TH-Cre transgenic rat model of pretangle AD, we attempted to model the earliest prodromal stages seen in humans. We infused an adeno-associated virus (AAV) with a transgene coding a pseudophosphorylated human tau, htauE14, into the LC, and examined the behavioural consequences using four behavioural tests to assess memory, at 1-3 and 4-6 months post-infusion. Selective htauE14-GFP expression in LC neurons was confirmed using double immunolabelling for tyrosine hydroxylase and green fluorescent protein (GFP). We showed that >93% of LC neurons expressed GFP at 1-3 and 4-6 months postinfusion. Using an antibody against dopamine-b-hydroxylase, we showed higher relative optical density for LC-htauE14 infused rats at 1-3 months post-infusion in CA1 and the subgranular zone, suggesting htauE14-mediated changes in LC projections. Behavioural assays indicate subtle, sex-dependent impairment on hippocampal-dependent spatial memory. These results indicate that AAV-htauE14 is selectively expressed in LC neurons and can modify noradrenergic input to memory structures. Behavioural deficits may become more apparent if the LC-mediated projections are lost as animals age.

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