The behavioral effects of virally induced human tau expression in the locus coeruleus of TgF344‐AD rats

Abstract

AbstractBackgroundAberrant tau in the locus coeruleus (LC) is one of the first detectable neuropathological changes in Alzheimer’s disease (AD). Ubiquitous expression of mutant tau exacerbates pathological and cognitive impairments in rodent models of AD, but the consequences of wild‐type (WT) human tau expression in the LC is unknown. LC dysfunction has been linked to neuropsychiatric disorders and cognitive impairments that are relevant to AD, including sleep disorders, depression, anxiety, and memory loss. TgF344 AD rats are a transgenic rat model of AD that express APPSwe and PS1DE9 mutations and develop age‐dependent amyloid and tau pathology, neuroinflammation, cell death, and memory impairments that closely resemble humans with AD. We took advantage of this clinically‐relevant AD rat model to investigate the pathological and behavioral consequences of early human WT tau expression in the LC of TgF344 AD rats.MethodAt 2 months of age, TgF344 AD rats and WT littermates received bilateral LC infusions of human tau or mCherry control virus driven by the LC‐specific PRSx8 promotor. When rats were 6‐7 months of age, behavioral assays were administered to assess arousal (sleep latency), anxiety (open field, elevated plus maze, and novelty suppressed feeding), depression (forced swim task), and memory (Morris water maze and fear conditioning). Tau pathology in the LC was also evaluated by immunohistochemistry.ResultPreliminary analyses suggest that the behavioral consequence of human tau expression in the LC may interact with genotype. Specifically, TgF344‐AD rats that received human tau virus infusions had reduced freezing during cued and contextual fear conditioning tests compared to TgF344 AD rats that received control virus. By contrast, freezing behavior in WT rats was not influenced by human tau infusions in the LC. Additional analyses to evaluate group differences in measures of arousal, anxiety, and depression tasks are still being analyzed. Rats that received human tau virus showed tau pathology in the LC that was reminiscent of that observed in early human AD.ConclusionTau in the LC may contribute to early behavioral symptoms of AD that occur before widespread neuropathology and neurodegeneration occurs.