Amelioration Mechanisms of Neurodegenerative Process in Niemann-Pick Disease type C1

Abstract

Niemann-Pick disease type C (NPC) is an incurable neurodegenerative disorder with disrupted lipid trafficking and it is characterized by progressive neurological deterioration leading to premature death. Therefore, the primary goal of my study is to understand the underlying mechanisms of the neuropathology and to suggest the novel treatment strategies for this incurable disease. In this purpose, I evaluated the therapeutic potential of (1) human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and (2) microglial inhibitor for NPC management using NPC1 mice model. In the first study, I hypothesized that hUCB-MSCs have multifunctional abilities to improve the neurological symptoms of NPC1, the main subtype of NPC. To test this hypothesis, hUCB-MSCs were directly transplanted into the hippocampus of NPC1 mice model at the early asymptomatic stage. This transplantation resulted in improvement of motor function in the Rota-rod test and recovery of impaired cholesterol homeostasis via stimulating the cholesterol efflux system of the NPC1 mice. In the hippocampus, hUCB-MSCs increased the neuronal survival and proliferation while some of treated cells underwent in vivo transdifferentiation into functional neurons with electrophysiological activity in whole-cell patch clamping. Further, hUCB-MSCs reduced Purkinje neuronal loss, the hallmark of NPC1 neuropathic signs, by suppressing inflammatory- and apoptotic signaling in the cerebellum. I found that neuroprotective actions of hUCB-MSCs were resulted from enhanced cell-survival signals including PI3K/AKT- and JAK2/STAT3 pathways as well as from corrected expression levels of GABA/glutamate transporters followed by decreased excitotoxicity in the NPC1-affected brain. In the second study, I focused on the pathology of NPC1-related olfactory bulb (OB), the least studied area in the NPC1-affected brain, to provide more novel findings in the field of NPC1. NPC1 mutants at 7 weeks of age showed a distinct olfactory impairment in the buried food test when compared with age-matched WT controls. I found the marked loss of olfactory sensory neurons and dopaminergic periglomerular neurons within the NPC1-OB, suggesting that NPC1 dysfunction impairs the integrity of the olfactory structure. The gradual denervation of olfactory sensory neurons in NPC1 mice led to a reduction in the neuroblast population within the OB

however, the total number of proliferating cells was found to be increased because microglia extensively accumulated in the NPC1-OB along with pro-inflammatory cytokines, including IL-1β and TNF-α, as the disease progresses. Therefore, then I evaluated the effects of the anti-inflammatory drug CsA on olfactory dysfunction in NPC1 mice to investigate the possible role of microgliosis on olfaction. My experiments revealed that treatment with CsA prevented reactive microgliosis, restored the proliferative capacity of neuroblasts and increased the number of newly generated OB interneurons. In addition, NPC mice displayed an improvement in overall performance in the buried food test after the chronic administration of CsA. Taken together, these findings imply that (1) direct transplantation of hUCB-MSCs into the NPC1-affected mouse brain reduces neuropathies including cholesterol imbalance and neural death both in the cerebrum and cerebellum and (2) microglial inhibition using immunosuppressive agent attenuates of olfactory impairment in NPC1 mice via the regulation of neuronal turnover in the OB. Therefore, my study suggests novel therapeutic approaches for the amelioration of neurodegenerative symptoms in NPC1.