Dataset Information

Serum neurofilament light reveals the contraction from widespread to lesion-bound neuroaxonal injury during autoimmune neuroinflammation

ABSTRACT: Blood-based neurofilament light (sNfL) indicates neuroaxonal injury in multiple sclerosis and is on the cusp of being implemented into clinical routine. However, anatomical origins and pathophysiological mechanisms of NfL release during acute relapses and later chronic disease stages are still poorly understood. Here, we applied immunohistochemistry, single molecule array, spatial transcriptomics and microglia/axon co-cultures to gain insight into spatio-temporal NfL release in experimental autoimmune encephalomyelitis (EAE). Results: Association of spinal cord white matter lesions and sNfL levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: In chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions, but showed a widespread distribution in early EAE. Followingthis spatio-temporal pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and micro-glia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro. Interpretation: Our data demonstrate that sNfL release in EAE driven by CNS myeloid cells exhibits progress in a disease stage-dependent centripetal manner from normal-appearing white matter to focal white matter lesions. These findings may further aid the interpretation of elevated sNfL levels in multiple sclerosis patients at different disease stages.

ORGANISM(S): Mus musculus

PROVIDER: GSE226591 | GEO | 2023/11/22

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathogenic mechanisms. Laser capture microdissection coupled to proteomics was used to interrogate spatially preserved changes in formalin-fixed paraffin-embedded brain tissue from chronic MS individuals and controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions. In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. Notably, a subset of proteins that were altered in MS white matter indicate altered lipid metabolism. Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. These findings highlight the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of pathologically distinct regions of MS brain tissue. Identification of spatially resolved changes in the proteome of MS brain tissue should aid in the understanding of pathophysiological mechanisms and the development of novel therapies.

Dataset Information

Serum neurofilament light reveals the contraction from widespread to lesion-bound neuroaxonal injury during autoimmune neuroinflammation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets