gms | German Medical Science

Introduction: Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 gene affects the cholesterol homeostasis and the transport of cholesterol and glycosphingolipids from late endosomes/ lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders. Previous findings confirm severe morphological and immunohistochemical alterations in the olfactory system of NPC1^-/- mutant mice compared with healthy controls (NPC1^+/+). The application of a combination therapy with miglustat and allopregnanolone/cyclodextrin has previously been shown to delay the onset of neurological symptoms in NPC1^-/- mice.

Objectives: We investigated alterations in the morphology and immunohistochemistry of the olfactory epithelium (OE) of NPC1^-/- mutant mice and NPC1^+/+ controls. Additionally, we compared the impact of a combination therapy (COMBI) with miglustat, cyclodextrin and allopreganolone with a monotherapy with cyclodextrin (Cyclo).

Materials & Methods: Using a BrdU protocol and immunohistochemistry with antibodies against BrdU, olfactory marker protein (OMP) and caspase-3, we determined cell densities of proliferating cells, mature olfactory receptor neurons (ORNs) and apoptotic cells on transverse sections of the OE of 8 weeks old untreated, COMBI-treated and Cyclo-treated NPC1^-/- mutants and respective NPC1^+/+ controls.

Results: Stereological analyses showed an enhanced apoptosis and a drastic loss of mature ORNs in NPC1^-/-, despite an increased proliferation. Both therapies revealed a substantial morphological improvement by an increased number of ORNs and proliferating cells and a reduction of apoptosis, however, without complete normalization to the NPC1^+/+ level.

NPC1^+/+ showed a significant, therapy-induced proliferation increase. Whereas COMBI-treated mice showed less newly formed cells than Cyclo-treated mice, the latter revealed less mature ORNs and enhanced apoptosis.

Conclusion: Severe immunohistochemical alterations of mutant mice were reversed by both therapies, COMBI and Cyclo. Both therapies induced significant proliferation and apoptosis in NPC1^+/+ that may be attributed to cyclodextrin.