Loss of Tau Expression Attenuates Neurodegeneration Associated with Α-Synucleinopathy

Background: Neuronal dysfunction and degeneration linked to alpha-synuclein (alpha S) pathology is thought to be responsible for the progressive nature of Parkinson's disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between alpha S pathology and tau abnormalities. We recently showed that A53T mutant human alpha S (Hu alpha S) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of alpha S pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of alpha S pathology (alpha-synucleinopathy) using a transgenic mouse model of alpha-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant Hu alpha S (TgA53T) were crossed with mTau(-/-) mice to generate TgA53T/mTau(-/-). To achieve more uniform induction of alpha-synucleinopathy in mice, we used intramuscular injections of alpha S preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau(-/-), and mTau(-/-) mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of alpha-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 alpha S aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions: Collectively, our data suggest that tau is likely acting downstream of alpha S pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in alpha-synucleinopathies to identify novel disease-modifying therapeutic strategies.