Therapeutic reactivation of hippocampal progenitors reverse cognition decline in mice with progressive brain demyelination.

Chronic brain demyelination and neurodegeneration are hallmarks of progressive multiple sclerosis (MS) that underlie cognitive impairments. Neural precursor cells (NPCs) in the hippocampus support cognition through neurogenesis. With MS chronicity, neurogenesis declines leading to memory impairments. The mechanisms that drive NPC quiescence in MS are largely unknown. Here, we link downregulation of neuregulin-1 (NRG-1) to diminished self-renewal, activity and neurogenesis of NPCs, and hippocampal neurodegeneration and memory decline in mice with chronic demyelination. NRG-1 is a key signaling protein for neural differentiation and function that we previously reported its dysregulation in chronic active lesions of human secondary progressive MS (SPMS). We show that NRG-1 restoration reactivates NPCs and foster hippocampal repair by supporting neurogenesis, neuronal complexity, synaptogenesis, and remyelination that reverse memory impairments. Compared with Siponimod, a current disease modifying therapy for SPMS, NRG-1 achieved greater and multifaceted reparative effects, highlighting its potential as a regenerative therapy for progressive MS.