Alterations in the blood–spinal cord barrier in TDP-43 conditional knockout mice

• The blood–spinal cord barrier (BSCB) keeps the homeostasis for the spinal parenchyma.
• The loss-of-function of TDP-43 protein contributes to the pathogenesis of ALS.
• We pathologically studied the BSCB of TDP-43 conditional knockout (TDP CKO) mice.
• The temporary BSCB breakdown is seen at the early symptomatic stage in TDP CKO mice.
• The BSCB disruption may contribute to the motor neuron degeneration in TDP CKO mice.

We investigated whether the loss of motor neuron-specific TDP-43 protein causes any change in the blood–spinal cord barrier (BSCB) in the spinal cord of TDP-43 conditional knockout (TDP CKO) mice. The TDP CKO mice were divided into four groups: early presymptomatic, late presymptomatic, early symptomatic, and late symptomatic stages. The spinal cords were pathologically examined. TDP CKO mice showed the activation of MAC-2 (macrophages/microglia) and fibrinogen exclusively in the anterior horn from the early symptomatic through the late symptomatic stages. Immunohistochemical and western blot analyses detected no reduction in tight junction proteins in TDP CKO mice as compared to age-matched wild-type mice at any stage. Electron-microscopically, TDP CKO mice showed vacuoles in the cytoplasm of most endothelial cells at the early symptomatic stage. The endothelium occasionally exhibited swollen cytoplasm by edematous fluid with the intact tight junction. The cytoplasm of the pericytes was relatively well preserved in contrast to the endothelial disruption. Extravascular or perivascular spaces were frequently edematous and vacuolated. At other stages, the BSCB was well preserved as in the controls. Thus, the temporary and reversible breakdown of the BSCB with leakage or increased permeability at the early symptomatic stage observed in this study could be a direct pathogenic consequence of the loss of TDP-43 protein, and the temporal impairment of BSCB, in turn, might contribute to the motor neuron degeneration in TDP CKO mice.