Abstract Details

Title Synergistic neuropathology resulting from co-expression of TDP-43 and tau protein in vivo

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 1-002

Objective To investigate the effect of pathological proteins concurrently expressed in distinct neuronal populations in an animal model of neurodegenerative disease.

Background The presence of multiple pathological proteins associated with neurodegenerative disease may initiate more aggressive toxicity than either 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.

Design/Methods 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.

Results After expressing mutant TDP-43, rats displayed a motor hindlimb paralysis. Spinal cord pallor and atrophy was observed along with reduction in the total number of anterior horn motor neurons compared to TDP non-expressing and ChAT non-expressing controls. Both WT and Thr¹⁷⁵Asp GFP-tau pathology was observed in the hippocampus of GFP-tau expressing rats with a twofold increase when expressed in TDP-43 mutant rats compared to expression in wild-type rats.

Conclusions

Co-expression of toxic variants of TDP-43 and tau protein in distinct cell populations can exacerbate tau protein pathology.

Authors/Disclosures
Alexander J. Moszczynski, MD, PhD (Queen's University) PRESENTER	No disclosure on file
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Michael J. Strong, MD, FAAN (London Health Sciences Centre)	No disclosure on file
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