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Article type: Research Article
Authors: Vogels, Thomasa | Vargová, Grétab | Brezováková, Veronikab | Quint, Wim Hendricusa | Hromádka, Tomáša; b; *
Affiliations: [a] Axon Neuroscience R & D Services SE, Bratislava, Slovakia | [b] Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
Correspondence: [*] Correspondence to: Tomáš Hromádka, Axon Neuroscience R & D Services SE, Dvořákovo nábrežie 10, 81102 Bratislava, Slovakia. [email protected]; Institute of Neuroimmunology, Slovak Academy of Sciences, Dúbravská cesta 9, 84510 Bratislava, Slovakia. Tel.: +421 2 547 881 00; E-mail: [email protected].
Abstract: Background:Neuronal accumulation of hyperphosphorylated and truncated tau aggregates is one of the major defining factors and key drivers of neurodegeneration in Alzheimer’s disease and other tauopathies. Objective:We developed an AAV-induced model of tauopathy mediated by human truncated tau protein without familial frontotemporal dementia-related mutations to study tau propagation and the functional consequences of tau pathology. Methods:We performed targeted transductions of the hippocampus or entorhinal cortex in adult mice followed by histological analysis to study the progression of hippocampal tau pathology and tau spreading. We performed behavioral analysis of mice with AAV-induced hippocampal tau pathology. Results:AAV-induced hippocampal tau pathology was characterized by tau hyperphosphorylation (AT8 positivity), sarkosyl insolubility, and the presence of neurofibrillary tangles. AAV-induced tau pathology was associated with microgliosis and hypertrophic astrocytes in the absence of cognitive deficits. Additionally, the co-expression of mCherry fluorescent protein and human truncated tau enabled us to detect both local spreading of human tau and spreading from the entorhinal cortex to the synaptically connected dentate gyrus. Conclusion:Targeted delivery of AAV with truncated tau protein into subcortical and cortical structures of mammalian brains represents an efficient approach for creating temporally and spatially well-defined tau pathology suitable for in vivo studies of tau propagation and neuronal circuit deficits in Alzheimer’s disease.
Keywords: Adeno-associated virus, Alzheimer’s disease, dementia, mice, tau protein, tauopathies
DOI: 10.3233/JAD-200047
Journal: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 551-568, 2020
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