PET imaging in rats to discern temporal onset differences between 6-hydroxydopamine and tau gene vector neurodegeneration models

Abstract

We attempted to monitor the nigrostriatal dopaminergic system in rats with positron emission tomography (PET) during the progression of two experimental disease states. One model was 6-hydroxydopamine (6-OHDA) lesioning and the other was direct gene transfer of the microtubuleassociated protein tau to the substantia nigra using an adeno-associated virus vector (AAV9). The PET ligand was 6-[18F]fluoro-L-m-tyrosine (FMT), imaged prior to, and at two intervals after initiating dopaminergic neurodegeneration. The striatum was delineated with the aid of repeated PET imaging (FMT and sodium fluoride for bone), realignment to subsequent computed axial tomography scans, and registration to an atlas, which proved essential to tracking disease progression. The striata on the two sides of the brain were compared over time after unilateral lesioning treatments. 6-OHDA reduced uptake on the ipsilateral side relative to the untreated contralateral side at both 1 and 4 weeks after lesioning, while the AAV9 tau led to reduced uptake of the tracer in the striatum at 4 weeks, but not 1 week after treatment. The amplitude of the loss of FMT uptake in striatum at 4 weeks with either model was subtle relative to the postmortem histological analysis of the tissue, but the multimodal imaging analysis yielded statistical effects that matched well with the histology in terms of the timing of the loss of dopaminergic markers. Live longitudinal imaging successfully tracked two distinct types of disease progression in individual rats, although the FMT is not a sensitive ligand to monitor the extent of the lesion.

Adult-onset focal expression of mutated human tau in the hippocampus impairs spatial working memory of rats

“…A substantial literature documents the deleterious effects of transgenic P301L tau expression on mnemonic function [24–26,36,37,39,40,67,68]. The major finding of our study is that working memory on a spatial alternation task was significantly impaired by the transduction of hippocampal neurons with P301L tau virus vector.…”

“…The GFP filled neurons entirely, revealing isolated projections into the entorhinal cortex, thalamus, and cerebral cortex as well as intrahippocampal connections. Transduced neurons were found throughout the dorsal-ventral extent of the hippocampus observed at all septo-temporal levels of the hippocampal formation [37,56,57]. Numbers of neuron cell bodies ranged up to several hundred per section for both vectors.…”

“…The recombinant AAV9 serotype has been successfully used to induce P301L tau expression in rats and was associated with profound neurodegeneration [35–37]. Of note is the fact that the time course of mutant human tau expression with AAV9 is rapid, showing faster onset and stronger expression of P301L tau than AAV2 and AAV8 [36].…”

“…Of note is the fact that the time course of mutant human tau expression with AAV9 is rapid, showing faster onset and stronger expression of P301L tau than AAV2 and AAV8 [36]. AAV p301L tau is expressed by 1 week, neurotransmitter loss can be observed by 2 weeks, and behavioral effects are evident by 3–4 weeks after transduction [37]. …”

Next generation tau models in Alzheimer's disease research – virus based gene delivery systems

“…AAV9 and/or AAV10 vectors also show early expression of tau accompanied by robust loss of nigrostriatal system when compared to AAV2 tau vector, mainly in the form of dopaminergic and GABAergic neuron loss (Klein et al, 2008(Klein et al, , 2009. This effect was not observed using equal doses of green fluorescent protein (GFP) or alpha-synuclein vectors suggesting that the pathological effect is highly specific to misfolded tau neurotoxicity.…”