1. Pharmacology of a novel tau aggregation inhibitor in animal models of tauopathies
- Author
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Dreesen, Eline Stefanie Elly, Riedel, Gernot, and Harrington, Charles
- Subjects
Alzheimer's disease ,Frontotemporal dementia ,Aggregation (Chemistry) ,Proteins - Abstract
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common types of dementia. The most frequently diagnosed subtype of FTD is the behavioural variant (bvFTD). Both AD and bvFTD present with a plethora of symptoms and share an underlying tauopathy. Tau forms aggregates in the brain and causes neurodegeneration, resulting in cognitive deficits, neuropsychiatric symptoms (NPS) and possible motor abnormalities. The exact mechanism of either disease is not yet fully understood, and more research is needed. This study focussed on the phenotypic presentation of, and the effects of a novel tau aggregation inhibitor (TAI) on the behavioural performance of two tauopathy models. L1 express a truncated tau fragment and exhibit spatial learning and memory deficits, representing AD pathology. L66 mice represent bvFTD pathology with the expression of full-length human tau with two point mutations, resulting in motor coordination and motor learning impairments. Previous research indicated a rescue effect of the novel TAI hydromethylthionine (HMT) on the behaviour of these mice, but interactions with existing AD treatments were not investigated. Clinical trials, however, revealed a negative interaction between HMT and AD therapeutics, warranting preclinical examination. Thus, the first aim of the present study was to investigate the impact of combination treatment of HMT and the acetylcholinesterase inhibitor Rivastigmine in L66 mice. No deficits were observed, however, and further validation studies were performed. A second aim of the present study was to study spatial cognitive deficits of both lines, and an assessment of therapeutic intervention with HMT. Differences in strategy used to perform the Barnes maze task were evident with L1, whereas, L66 performance was no different to controls. Treatment with HMT induced no effect. A final aim was the investigation of NPS in both models, similar to those seen in AD and bvFTD patients. An anxiety phenotype was established for L1 mice, while L66 animals presented with apathy-like behaviour.
- Published
- 2021