Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann-Pick disease type C1 mice.

Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann-Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.

Donepezil enhances Purkinje cell survival and alleviates motor dysfunction by inhibiting cholesterol synthesis in a murine model of Niemann Pick disease type C.

Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3-hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC.

JNK Activation by Up-Regulation of iNOS on Cholesterol Accumulation Limits Neurogenesis and Induces Region-Specific DNA Damage Responses in the Subventricular Zone of NPC Mice.

Abstract Aims: We explore the region-specific impact of nitric oxide (NO) on adult neural stem cell (aNSC) niches with regard to neurogenesis and NSC damage and investigate the underlying mechanisms in Niemann-Pick disease type C (NPC) mice. Results: Among the two anatomical stem-cell niches of the brain, subventricular zone (SVZ)-derived aNSCs enhanced c-Jun N-terminal kinase (JNK) activity because of excessive NO production by the cholesterol accumulation. Activated JNK interacts with γH2AX, a marker for DNA damage; however, almost none of the aNSCs in the dentate gyrus (DG) showed either JNK signaling activation or abundant DNA damage. SVZ-derived aNSCs were protected from DNA damage by the treatment of Nω-nitro-L-arginine methyl ester (L-NAME), a NO synthase (NOS) inhibitor, both in vitro and in vivo. We also observed that U18666A, an inducer of cholesterol accumulation, increased inducible NOS expression, JNK activation, and DNA damage in the wild type (WT)-aNSCs. Interestingly, we found that endogenous cholesterol efflux transporters and their regulator were less activated in the SVZ than in the DG, in both WT and NPC mice. This result explains the high vulnerability of SVZ-derived aNSCs to the cholesterol imbalance as observed in NPC mice. Innovation and Conclusion: In this study, we demonstrated that the SVZ-derived aNSCs might be major targets of NPC. Significantly, aNSCs showed different responses depending on their anatomical origins due to dissimilarities in their cholesterol transporting system and NO-dependent JNK activation. These findings can contribute to the understanding of the region-specific nature of the two SVZ and DG neurogenic niches. Antioxid. Redox Signal. 00, 000-000.