Role of Aging and Amyloid in Viral Vector Mediated Tauopathy

Abstract

Aging is a major risk factor for Alzheimer’s disease (AD) and related dementias. We used viral vectors to initiate tau over-expression in mice of different ages. Delivery of tau containing the FTD-associated mutation P301L produced tauopathy in nontransgenic C57BL/6Nia mice, including increased phosphorylated tau and formation of neurofibrillary tangles. Surprisingly, tauopathy was only modestly increased in aged mice, and these increases seem insufficient to account for the exponential increase in risk of AD in the aged. Using viral constructs over-expressing different tau variants, we observed that 4R2N tau (without mutations) was neurotoxic, while P301L tau aggregated more. Rapamycin was used to slow the rate of biological aging, then tauopathy was induced by viral over-expression of P301L tau. The magnitude of the tauopathy produced was not affected by prior long-term treatment with rapamycin. Finally, we used viral constructs with capsids allowing uptake across the blood brain barrier to deliver P301L tau intravenously, producing modest 2-fold tau over-expression. Nontransgenic mice developed tauopathy (increased phosphorylated and aggregated tau). However, mice with pre-exising amyloid deposits developed greater tauopathy. This model will be useful to explore mechanisms of and treatments for amyloid- induced tauopathy.