targeting astrocytes to prevent neurodegeneration

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frodo
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targeting astrocytes to prevent neurodegeneration

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Targeting astrocytes to prevent neurodegeneration in patients with multiple sclerosis

https://www.tdx.cat/handle/10803/674407

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). Most MS patients initially have an inflammatory phase characterized by periods of clinical relapses and remissions. Over time, a large proportion of patients will enter a progressive neurodegenerative phase of the disease characterized by sustained and irreversible neurological deterioration.

Currently available therapies for MS patients are highly effective to suppress inflammation, but largely fail to prevent the neurodegenerative component that inevitably leads to disease progression. Despite that reactive astrogliosis is now one of the pathological hallmarks in MS, astrocytes have always been considered as static bystander cells. However, astrocytes are involved in many important CNS functions, such as ion, pH and water homeostasis, maintenance of blood-brain barrier properties, control of energy supply to neurons, and regulation of function and formation of synapses. Furthermore, compelling evidence points to astrocytes as key contributors to the neurodegenerative component observed in MS.

However, the mechanisms underlying the regulation of astrocytic responses remain unknown. In the present study, we aimed to investigate how inflammation in MS induces astrocyte reactivity modulating the astrocytic response that leads to neuronal damage. We report an exhaustive molecular and functional characterization of astrocyte reactivity following exposure to cerebrospinal fluid (CSF) from MS patients classified according to the degree of inflammatory activity. We showed that mouse astrocytes exposed to CSF from patients with high inflammatory activity (MS-High) exhibited a specific pro-inflammatory reactive state that was characterized by enhanced nuclear factor kappa B (NF-кB) signalling. This reactive astrocyte state conferred an aberrant response through an altered pro-inflammatory secretome that drove neuronal dysfunction and impaired synaptic plasticity.

SerpinE1 was identified as a potential downstream mediator of the non-cell-autonomous toxic effect on neuronal function based on its significant up-regulation in secretomes from astrocytes exposed to CSF from MS-High patients. Furthermore, we identified chitinase 3-like 1 (CHI3L1) as a potential upstream modulator of astrocyte reactivity via activation of NF-kB signalling based on its significantly increased levels in the CSF from MS-High patients.

Taken together, our findings indicate that the inflammatory microenvironment in the CNS of MS patients can induce specific reactive astrocyte states that trigger neuronal degeneration and may ultimately contribute to disease progression.
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