Progression of multiple sclerosis: The role of microglia and neurons.

TY - THES

T1 - Progression of multiple sclerosis: The role of microglia and neurons.

AU - van den Bosch, Aletta

PY - 2024/11/7

Y1 - 2024/11/7

N2 - Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelinating lesions in the central nervous system (CNS). This thesis explores the role of microglia and neurons in lesion formation, expansion, and repair in post mortem human brain tissue.Part 1 highlights how loss of microglial homeostasis, possibly due to decreased neuronal CD200 and CD47 expression, and myelin decompaction in normal-appearing brain tissue may initiate lesion formation. Microglia nodules are identified as possible start of MS lesions, exhibiting inflammation and early demyelination. Part 2 investigates lesion heterogeneity, showing that lesions with foamy microglia are expanding and are associated with more axonal damage, while lesions with ramified microglia are associated with remyelination and repair. Lesions with foamy microglia are linked to adaptive immune activity and failure of remyelination, whereas those with ramified microglia promote regeneration. Part 3 shows the biological relevance of single nucleotide polymorphism (SNP) rs10191329, validating its association with a more severe disease course. Homozygous risk carriers have a higher incidence of active lesions with foamy microglia, increased T-cell presence, and greater tissue damage, implicating the neighbor gene products ZNF638 and dysferlin in MS disability accrual.Overall, this thesis uncovers key molecular pathways and cellular mechanisms that contribute to MS lesion formation, expansion, and repair. The reported research highlights the significance of microglia homeostasis, myelin integrity, and genetic factors in MS progression, offering insights for the development of new therapeutic strategies.

AB - Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelinating lesions in the central nervous system (CNS). This thesis explores the role of microglia and neurons in lesion formation, expansion, and repair in post mortem human brain tissue.Part 1 highlights how loss of microglial homeostasis, possibly due to decreased neuronal CD200 and CD47 expression, and myelin decompaction in normal-appearing brain tissue may initiate lesion formation. Microglia nodules are identified as possible start of MS lesions, exhibiting inflammation and early demyelination. Part 2 investigates lesion heterogeneity, showing that lesions with foamy microglia are expanding and are associated with more axonal damage, while lesions with ramified microglia are associated with remyelination and repair. Lesions with foamy microglia are linked to adaptive immune activity and failure of remyelination, whereas those with ramified microglia promote regeneration. Part 3 shows the biological relevance of single nucleotide polymorphism (SNP) rs10191329, validating its association with a more severe disease course. Homozygous risk carriers have a higher incidence of active lesions with foamy microglia, increased T-cell presence, and greater tissue damage, implicating the neighbor gene products ZNF638 and dysferlin in MS disability accrual.Overall, this thesis uncovers key molecular pathways and cellular mechanisms that contribute to MS lesion formation, expansion, and repair. The reported research highlights the significance of microglia homeostasis, myelin integrity, and genetic factors in MS progression, offering insights for the development of new therapeutic strategies.

M3 - PhD thesis

ER -