Co-expression of TDP-43 and tau protein induces synergistic neurotoxicity in vivo Moszczynski AJ1, Volkening K1, Harvey M1, Fulcher N2, DeOliviera C2, McCunn P3, Bartha R3, Schmid S2, Strong MJ1 1Molecular Medicine research group, Robarts Research Institute; 2Department of Anatomy and Cellular Biology, Schulich School of Medicine and Dentistry, University of Western Ontario; 3Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario
The presence of multiple pathological proteins associated with neurodegenerative disease may initiate more aggressive toxicity, and activate pathological processes that are not initiated by any pathological protein alone. Two proteins associated pathological inclusions in multiple neurodegenerative diseases are microtubule associated protein tau (tau) and TAR-DNA binding protein of 43 kDa (TDP-43). We hypothesize that co-expression of toxic variants of tau and TDP-43 will result in increased pathological inclusions of both proteins and increased neuronal death. Transgenic female Sprague-Dawley rats were generated to inducibly express mutant human TDP-43 (M337V) using the choline acetyltransferase (ChAT)- tetracycline response element (TRE) driver with activity modulating tetracycline-controlled transactivator (tTA). Adult rats were injected with GFP-tagged tau protein constructs in an adeno-associated virus (AAV9) vector through bilateral stereotaxic injection into the hippocampus. Injected tau constructs were: wild type GFP-tagged 2N4R human tau (WT; n=10), GFP-tagged Thr175Asp 2N4R human tau (pseudophosphorylated, toxic variant, n=10), and GFP (control, n=10). Six months post-injection, mutant TDP-43 expression was induced for 30 days followed by euthanization of rats. Brain and spinal cord tissue was removed and fixed prior to immunohistochemical analysis (IHC) using antibodies against human TDP-43 and GFP to probe for mutant TDP-43 and GFP-tau respectively. Preliminary analysis (n=3 per group) revealed TDP-43 and GFP-tau pathology in the hippocampus of GFP-tau expressing rats. TDP-43 staining was more intense and displayed non-spherical nuclear shape in regions co-expressing GFP-tau. No pathology was observed in GFP only expressing rats. These data suggest that co-expression of TDP-43 and tau protein exacerbate the pathology associated with either individual protein. Ongoing studies further investigate the extent of pathology, co-localization and overlap of expression.
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