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

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It's as if our being was a chimera of two organisms, one would be the body and the other would be the central nervous system (CNS).

The CNS blood circulatory system is separated from the body system by nearly impervious barriers except for very small molecules. The CNS has it's own immune system (astrocystes), it has it's own clearing system known as the glymphatic system.

Multiple lines of evidence suggest possible impairment of the glymphatic system in several neurodegenerative diseases. This makes sense in a field where little makes sense. If those diseases are characterized by misfolded proteins clumps, at least in extracellular medium as in Alzheimer, then the question of the quality of the clearance mechanism is of utmost importance.

To investigate this, scientists used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of amyotrophic lateral sclerosis (ALS), in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43, mimicking the key pathology implicated in ALS.

Recent evidence points to self-propagation of TDP-43 misfolding, either by the circulatory system, cell-to-cell contact, or via the interstitial or cerebrospinal fluids (CSF).

The glymphatic system is largely dormant during wakefulness but highly active during sleep, working to clear waste byproducts from the brain through the flow of CSF.

Preclinical studies have shown that amyloid-β, a protein implicated in Alzheimer’s disease, is cleared from the brain by the glymphatic system and that in aged mice, amyloid-β clearance is dramatically slowed.

As the prevalence of ALS also increases with age, sleep disturbances are exceedingly common in ALS and given that a single night of sleep deprivation can result in amyloid-β accumulation linked with Alzheimer’s disease, the authors hypothesized that glymphatic clearance is also impaired in ALS.

Their results demonstrate that the TDP-43 mice, in addition of usual symptoms of ALS, exhibited significantly altered glymphatic function very early in the disease course.

Yet the scientists didn't try to verify if the mice glyphatic function would be restored if the mice were feed again with doxycycline.

The authors do no attempt either to explain the relation between the genetically forced expression of TDP-43 in cytoplasm and induction of reduced glymphatic function. Indeed what would be more interesting is a proof that a reduced glymphatic function results in accumulation of misfolded proteins in cytoplasm.

So this article does not bring much additional knowledge, yet if sleeping helps removing the misfolded protein clumps, one could imagine that sleep drugs could help to manage ALS.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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