Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice
Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43....
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000488 |
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| author | Akram Zamani Adam K. Walker David K. Wright |
| author_facet | Akram Zamani Adam K. Walker David K. Wright |
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| description | Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target. |
| format | Article |
| id | doaj-art-040cb5a0e32b4d59a9d4a05fb190370f |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-040cb5a0e32b4d59a9d4a05fb190370f2025-02-08T04:59:34ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106832Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 miceAkram Zamani0Adam K. Walker1David K. Wright2Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, AustraliaQueensland Brain Institute, The University of Queensland, QLD 4072, Australia; Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, AustraliaDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Corresponding author at: Department of Neuroscience, The School of Translational Medicine, Monash University, The Alfred Centre, 99 Commercial Road, VIC 3004, Australia.Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.http://www.sciencedirect.com/science/article/pii/S0969996125000488Motor neuron diseaseProteinopathyWaste clearanceDiffusion weighted imaging |
| spellingShingle | Akram Zamani Adam K. Walker David K. Wright Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice Neurobiology of Disease Motor neuron disease Proteinopathy Waste clearance Diffusion weighted imaging |
| title | Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice |
| title_full | Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice |
| title_fullStr | Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice |
| title_full_unstemmed | Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice |
| title_short | Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice |
| title_sort | glymphatic dysfunction and neurodegeneration in als longitudinal insights from rnls8 tdp 43 mice |
| topic | Motor neuron disease Proteinopathy Waste clearance Diffusion weighted imaging |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000488 |
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