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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.

Alzheimer's disease is currently the most common neurodegenerative disorder, characterized by distinct cognitive and sensory deficits. The underlying pathogenetic mechanisms, however, still remain elusive. How the molecular and morphological changes associated with Alzheimer's disease affect information processing in neuronal circuits and translate into cognitive dysfunction is unclear. Inhibitory interneurons have recently emerged as one of the earliest and important culprits in mediating dysfunction of neuronal circuits in neurodegeneration. Amyloid-beta and tau protein have been both linked to interneuron dysfunction, and likely play an important, albeit unknown, role in mediating changes in the overall activity of neuronal circuits. Resolving the role of inhibitory interneurons in neurodegeneration-specific changes in neuronal activity is crucial for understanding the impact of Alzheimer's disease on brain function and even for possible identification of effective treatments and diagnostic techniques (Ref. 63).

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