A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC) is a rare and fatal neurological disorder caused by mutations in Npc1 or Npc2, with Npc1 accounting for 95% of cases. These mutations result in the functional loss of their respective proteins, causing cellular abnormalities characterized by disrupted lipid dysregulation, calcium dysfunction, elevated damage associated molecular patterns (DAMPs), and a pro-inflammatory environment. This cellular pathology ultimately triggers neurodegeneration, with the cerebellum being the earliest and most affected region. We have recently shown atypical activation of interferon signaling in the presymptomatic Npc1-/- mouse cerebellum and, to a lesser extent, in the cerebral cortex. In addition, we reported that the Amyloid Precursor Protein (APP) is an NPC disease modifier. Loss of APP function leads to widespread neurodegeneration in the NPC brain, including exacerbated interferon signaling in the cerebellum. To better understand the role of APP as a disease modifier throughout the NPC brain, here we carried out a transcriptomic analysis of the cerebral cortex and cerebellum from 3-week-old Npc1-/- mice as well as age-matched controls in the presence and absence of APP. We report differential effects of APP loss of function in the cerebral cortex and cerebellum, including cholesterol and tau dysregulation, in both brain regions. Our findings demonstrate a novel link between APP loss and early pathogenic mechanisms in NPC.

Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic Npc1-/- mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic Npc1-/- mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease.