Progressive neuronal loss in the ventral posterior lateral and medial nuclei of thalamus in Niemann-Pick disease type C mouse brain.

Niemann-Pick disease type C (NP-C) disease is a progressive and fatal neurological disorder characterized by accumulation of cholesterol and glycosphingolipids in peripheral tissues and that of glycosphingolipids in the brain. A C57BL/KsJ-npc1(spm) mutant strain is a genetically authentic model of NP-C. This study investigated neuronal cell loss and lipid accumulation in the npc1(spm) mouse brain. Nissl-staining revealed abundant swollen neurons in the neocortex, piriform cortex, hippocampus and basal ganglia at 3-4 wk of age. In addition to loss of the Purkinje cells, we found a conspicuous cell loss in the ventral posterial lateral (VPL) and medial (VPM) nuclei of thalamus, which became apparent after 4-5 wk. Biochemical analyses revealed no increase of cholesterol in the lipid extracts whereas a substantial accumulation of cholesterol was detectable in most of the large neurons by filipin staining in the brain of homozygous mice. In contrast to the diffuse staining pattern in normal brains, the neuropils of the neurons in the brain of homozygous mice were stained in a punctate pattern. The ubiquitous accumulation excludes a direct role of cholesterol in the progressive neuronal loss in the Purkinje cell layer and in the VPL and VPM of the thalamus.

Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma.

BACKGROUND/AIM: The protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. METHODS: Immunohistochemistry and a semiquantitative scoring method in normal liver and biliary diseases were used for the investigation. RESULTS: In "normal" adult livers (n=10), intrahepatic bile ducts were negative for PKR. In normal fetal livers (n=25), primitive biliary epithelia were almost negative for PKR. In primary biliary cirrhosis (PBC) (n=30), damaged bile ducts were frequently positive for PKR, while uninvolved bile ducts were negative. In hepatolithiasis (n=27), proliferated bile ducts were positive for PKR, and the PKR score correlated with the degree of proliferation. In cholangiocarcinoma (CC) (n=44), PKR expression was frequently noted, and the PKR score correlated with good differentiation of CC, being highest in well-differentiated CC and lowest in poorly-differentiated CC. The PKR score decreased in the following order: CC (mean PKR score=3.96), hepatolithiasis (2.56), PBC (1.60), normal fetal liver (0.40), and normal adult livers (0.00). The PKR expression in hepatocytes was "baseline" in normal adult livers, while moderately increased in fetal livers, PBC, hepatolithiasis and CC. CONCLUSIONS: Although the significance of these data is unclear, they suggest (i) that PKR is absent in bile ducts in normal adult and fetal livers, (ii) that PKR in bile duct cells newly emerges or increases in PBC, hepatolithiasis, and CC, (iii) that PKR accumulates in damaged bile ducts in PBC, (iv) that PKR increases in parallel with biliary cell proliferation in hepatolithiasis, and (v) that PKR expression correlates with differentiation in CC. PKR expression in intrahepatic bile ducts seems to be associated with inflammation or cell proliferation of the bile duct cells.