Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

Chronic brain demyelination and neurodegeneration are pathological hallmarks of progressive multiple sclerosis (MS) that underlie cognitive impairments. Neural precursor cells (NPCs) that reside in the hippocampus support cognition through adult neurogenesis. However, with MS chronicity, hippocampal neurogenesis declines that results in memory and learning impairments. Currently, the underlying mechanisms that drive NPC senescence in chronic MS are largely unknown. Here, we have linked downregulation of Neuregulin-1beta 1 (Nrg-1β1) to hippocampal neurodegeneration, neurogenic decline and memory impairment in mice with chronic brain demyelination. Nrg-1β1 is a key factor for neural differentiation that we previously reported its downregulation in chronic human MS lesions. Here, extensive in vivo and in vitro characterizations revealed that therapeutic restoration of Nrg-1β1 can reactivate NPCs and foster hippocampal repair by neurogenesis, synapse reassembly and remyelination that reverses memory impairments. Transcriptomics of NPC progenies confirmed upregulation of genes associated with myelination, synaptic resilience, and cellular homeostasis, underscoring the potential of Nrg-1β1 in activating regenerative mechanisms within the chronically demyelinated hippocampus. Moreover, in comparison with Siponimod, a leading disease modifying therapy for secondary progressive MS, Nrg1β1 treatment achieved multifaceted and greater reparative effects. These new findings introduce Nrg1β1 as a disease relevant candidate with promising therapeutic potential for progressive MS.