Amyloid-β metabolism in Niemann-Pick C disease models and patients

Niemann-Pick type C (NPC) is a progressive neurodegenerative lysosomal disease with altered cellular lipid trafficking. The metabolism of amyloid-beta (A beta) - previously mainly studied in Alzheimer's disease - has been suggested to be altered in NPC. Here we aimed to perform a detailed characterization of metabolic products from the amyloid precursor protein (APP) in NPC models and patients. We used multiple analytical technologies, including immunoassays and immunoprecipitation followed by mass spectrometry (IP-MS) to characterize A beta peptides and soluble APP fragments (sAPP-alpha/beta) in cell media from pharmacologically (U18666A) and genetically (NPC1 (-/-) ) induced NPC cell models, and cerebrospinal fluid (CSF) from NPC cats and human patients. The pattern of A beta peptides and sAPP-alpha/beta fragments in cell media was differently affected by NPC-phenotype induced by U18666A treatment and by NPC1 (-/-) genotype. U18666A treatment increased the secreted media levels of sAPP-alpha, A beta X-40 and A beta X-42 and reduced the levels of sAPP-beta, A beta 1-40 and A beta 1-42, while IP-MS showed increased relative levels of A beta 5-38 and A beta 5-40 in response to treatment. NPC1 (-/-) cells had reduced media levels of sAPP-alpha and A beta 1-16, and increased levels of sAPP-beta. NPC cats had altered CSF distribution of A beta peptides compared with normal cats. Cats treated with the potential disease-modifying compound 2-hydroxypropyl-beta-cyclodextrin had increased relative levels of short A beta peptides including A beta 1-16 compared with untreated cats. NPC patients receiving beta-cyclodextrin had reduced levels over time of CSF A beta 1-42, A beta X-38, A beta X-40, A beta X-42 and sAPP-beta, as well as reduced levels of the axonal damage markers tau and phosphorylated tau. We conclude that NPC models have altered A beta metabolism, but with differences across experimental systems, suggesting that NPC1-loss of function, such as in NPC1 (-/-) cells, or NPC1-dysfunction, seen in NPC patients and cats as well as in U18666A-treated cells, may cause subtle but different effects on APP degradation pathways. The preliminary findings from NPC cats suggest that treatment with cyclodextrin may have an impact on APP processing pathways. CSF A beta, sAPP and tau biomarkers were dynamically altered over time in human NPC patients.