Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis

Abstract

Background Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43ΔNLS), mimicking the key pathology implicated in ALS. Methods Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor performance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna. Results Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss including gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this ALS-like phenotype, these mice have significantly disrupted glymphatic function. Conclusions Although the relationship between glymphatic clearance and ALS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of ALS.

Early and progressive dysfunction revealed by in vivo neurite imaging in the rNLS8 TDP-43 mouse model of ALS

“…These findings are also consistent with the results of our initial fixel -based analysis of these datasets ( Zamani et al, 2022 ). The term fixel refers to an individual fibre bundle within a voxel.…”

“…This study included data from 12 adult (10–12 weeks) male mice used in a previous study ( Zamani et al, 2022 ). Of these, 7 were NEFH+/NLS+ (rNLS8) double transgenic mice with Dox-suppressible expression of hTDP-43ΔNLS (referred to as ‘TDP-43 mice’ throughout) and the remaining 5 NEFH-/NLS + single transgenic littermates were used as controls (Jackson Laboratories NEFH-tTA line 8, stock #025397 and tetO-TARDBP* line 4, stock #014650).…”

“…DWI pre-processing and atlas construction was performed as described previously using MRtrix3 ( Tournier et al, 2019 ) and FSL’s eddy ( Andersson and Sotiropoulos, 2016 , Zamani et al, 2022 ). Pre-processed images were resized to 125 × 125 × 125 μm 3 using cubic interpolation and tensor fitting performed using MRtrix3.…”

“…Employing multimodal MRI, we recently demonstrated progressive neurodegeneration in an experimental model of ALS with neuronal doxycycline (Dox)-suppressible overexpression of human TDP-43 (hTDP-43) ( Zamani et al, 2022 ). These mice underwent in vivo MRI at 1- and 3- weeks following the initiation of hTDP-43 expression, including multi-shell DWI which was analyzed using multi-tissue constrained spherical deconvolution.…”

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

“…Experiments were conducted with approval from the Animal Ethics Committee of Macquarie University (#2016-026). For all other experiments, rNLS8 mice were produced from the intercross of homozygous tetO-hTDP-43ΔNLS line 4 mice with hemizygous NEFH-tTA line 8 mice both on a pure C57BL/6JAusb background following >10 generations of backcrossing and were fed with Dox-containing chow (200mg/kg, Specialty Feeds, Australia) (58). Experiments were conducted with approval from the Animal Ethics Committee of The University of Queensland (#QBI/131/18).…”