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Aged mice carriers of a recessive neurodegenerative disorder Niemann-Pick type C show tau hyperphosphorylation, endolysosomal dysfunction and neuroinflammation

Niemann-Pick type C disease (NPC) is a rare, recessive, fatal, lipid storage disorder caused by mutations in NPC1 or NPC2 genes. NPC1/NPC2 code for cholesterol transport proteins. Their dysfunction leads to accumulation of free cholesterol and other lipids within late endosomes/lysosomes. NPC disease is characterized by progressive neruodegeneration (of primarily Purkinje neurons in the cerebellum) and neuroinflammation (activation of astrocytes and microglia). The carriers of NPC disease are considered healthy, assuming that heterozygous NPC1/NPC2 mutations do not cause any symptoms. The goal of this work was to analyze whether the brains of NPC1 heterozygous mice show any pathological features of NPC disease, including accumulation of cholesterol, tau hyperphosphorylation, neurodegeneration and neuroinflammation. We hypothesized that the aged carriers of NPC1-mutant allele present several pathological features of NPC disease. To test this, we used the BALB/cNctr-Npc1N/+ mice (NPC1+/-, Jackson Laboratory, Bar Harbor, Maine, USA). Female and male NPC1+/- mice were mated to generate NPC1+/+ (wt, control) and to maintain NPC1+/- mice. The brains (cortex, hippocampus and cerebellum) of 40-, 60-, 80- and 100-weeks old NPC1+/- and NPC1+/+ mice were isolated and analyzed by western blotting and immunohistochemistry. Our results show that aged (60- and 100-weeks old) NPC1+/- mice show several key pathological features of NPC disease compared to aged-matched controls, including altered endolysosomal pathway, neuroinflammation and differences in tau hyperphosphorylation pattern. The analysis of younger NPC1+/- mice is underway to identify the earliest changes upon loss of single NPC1 allele. Our findings indicate that carriers of the autosomal recessive NPC disease may not be considered healthy, suggesting that human heterozygous NPC1 mutation may be a risk factor for neurodegenerative disorders in the aged population.

Niemann-Pick type C ; Alzheimer's disease ; tau ; endolysosomal disfunction ; neuroinflammation

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