Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion induced by permanent unilateral common carotid artery occlusion in mice was recently found to induce an age-dependent formation of insoluble cytoplasmic TDP-43 aggregates reminiscent of pathological changes found in human vascular dementia. In this model, the gradual deregulation of TDP-43 homeostasis in cortical neurons was associated with marked cognitive and motor deficits. To target the TDP-43-mediated toxicity in this model, we generated an adeno-associated virus vector encoding a single-chain antibody against TDP-43, called scFv-E6, designed for pan-neuronal transduction following intravenous administration. Injected prior to brain hypoperfusion, this tonic virus-mediated delivery of the scFv-E6 antibody reduced formation of cytoplasmic TDP-43 aggregates in cortical neurons, boosted levels of autophagy markers and attenuated microgliosis. Moreover, the novel object recognition and grip strength tests revealed that neuronal expression of scFv-E6 prevented the cognitive impairment and loss of motor performance caused by two-months of cerebral hypoperfusion. The robust protective effects of scFv-E6 antibody in this model suggest a key role of TDP-43 in neuronal damage and symptom phenotypes caused by chronic cerebral hypoperfusion. Accordingly, TDP-43 should be considered as a new therapeutic target in drug development, including antibody approaches, for treatment of vascular dementia.