VIRAL VECTOR-MEDIATED OVEREXPRESSION OF HUMAN TAU IN THE RAT LOCUS COERULEUS: TAU LONG-TERM EXPRESSION AND PATHOLOGICAL CHANGES

Abstract

In Alzheimer's disease (AD), abnormal intraneuronal accumulation of tau protein starts in the locus coeruleus (LC), decades before onset of clinical symptoms. Interestingly, noradrenergic (NA) neurons in the LC degenerate early in the course of AD, leading to reduced cortical NA levels. In addition, NA plays an important role in the modulation of neuroinflammation, a process that appears early on in AD and is disease-aggravating. Taken together, this would suggest that the LC is a key player in the early AD pathogenesis. However, current transgenic rodents do not recapitulate the AD-like early accumulation of tau in the LC, preventing full understanding of the incipient stages of the disease. To address this, we generated rats overexpressing human tau in the LC using somatic transgenesis. Recombinant adeno-associated viral vectors (AAV9) encoding for either human wild-type tau, P301S mutant tau, or GFP under the control of the synthetic promoter PRSx8, were stereotaxically injected in the LC of 3 month-old Wistar rats. 12 months post injection, rats were perfused and their brains collected for immunohistochemical analyses. Histological analyses revealed stable protein expression in the LC, persisting 12 months after injection. Transgene was expressed throughout the LC and NA neurons were selectively transduced. Widespread GFP immunoreactivity was seen in fiber terminals of target regions, including cerebral cortex and hippocampus, ascending from LC neurons through the dorsal noradrenergic bundle. Importantly, tau hyperphosphorylation and conformational changes as seen in human AD and tauopathies were detected in the LC, as revealed by immunoreactivity to AT8, AT180, and MC1 antibodies, respectively. Targeted overexpression of human tau using somatic transgenesis constitutes a useful model to study the consequences of early tau accumulation in the LC. Combined with an AD-like model of amyloid pathology, this tool should shed light on the impact of an early LC dysfunction on AD pathology. Acknowledgments: The authors wish to acknowledge the following agencies for financial support: CIHR, FRQS, the Richard and Edith Strauss Canada Foundation, CONACyT and FRQNT.