ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice.

We previously demonstrated that macrophages exhibit endoplasmic reticulum fragmentation under cholesterol-rich conditions, which results in the generation of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1)-associated late endosomes/lysosomes (ACAT1-LE). ACAT1-LE efficiently esterify free cholesterol in loco, even with abnormal egress of free cholesterol from late endosomes. Because impaired free cholesterol transport from late endosomes results in Niemann-Pick type C disease (NPC), the induction of ACAT1-LE is a potential therapeutic intervention for NPC. To examine the effects of ACAT1-LE induction on intracellular cholesterol metabolism, we incubated bone marrow-derived macrophages possessing NPC phenotype (npc1 (-/-)) with methyl-ß-cyclodextrin-cholesterol complex (mßCD-cho), a cholesterol donor. Immunofluorescence confocal microscopy revealed that mßCD-cho treatment of npc1 (-/-) macrophages resulted in significant colocalization of signals from ACAT1 and lysosome-associated membrane protein 2, a late endosome/lysosome marker. npc1 (-/-) macrophages contained significant amounts of free cholesterol with negligible amounts of cholesteryl ester, while wild-type macrophages possessed the same amounts of both cholesterols. mßCD-cho treatment also induced marked restoration of cholesterol esterification activity. mßCD-cho administration in neonate npc1 (-/-) mice improved survival. These results indicate that ACAT1-LE induction in npc1 (-/-) mice corrects impaired intracellular cholesterol metabolism and that restoring cholesterol esterification improves prognosis of npc1 (-/-). These data suggest that ACAT1-LE induction is a potential alternative therapeutic strategy for NPC.

Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.

Macrophages in hyperlipidemic conditions accumulate cholesterol esters and develop into foamy transformed macrophages. During this transformation, macrophages demonstrate endoplasmic reticulum fragmentation and consequently produce acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1)-positive late endosomes (ACAT1-LE). ACAT1-LE-positive macrophages effectively esterify modified or native low-density lipoprotein-derived free cholesterol, which results in efficient cholesterol esterification as well as atherosclerotic plaque formation. These macrophages show significant cholesterol ester formation even when free cholesterol egress from late endosomes is impaired, which indicates that free cholesterol is esterified at ACAT1-LE. Genetic blockade of cholesterol egress from late endosomes causes Niemann-Pick disease type C (NPC), an inherited lysosomal storage disease with progressive neurodegeneration. Induction of ACAT1-LE in macrophages with the NPC phenotype led to significant recovery of cholesterol esterification. In addition, in vivo ACAT1-LE induction significantly extended the lifespan of mice with the NPC phenotype. Thus, ACAT1-LE not only regulates intracellular cholesterol metabolism but also ameliorates NPC pathophysiology.

Concomitant accumulation of α-synuclein and TDP-43 in a patient with corticobasal degeneration.

Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and α-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, α-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins.

[Successful treatment of Epstein-Barr virus-related encephalomyelitis with steroid and ganciclovir].

We report a 56-year-old man with encephalomyelitis due to Epstein-Barr virus (EBV). The patient suffered from fever and headache, and become somnolent on day 10. On day 18, following treatment with an antibiotic and aciclovir, a cerebrospinal fluid (CSF) examination revealed increased protein levels and lymphocytic pleocytosis. On day 25, he developed progressive tetraplegia, hypesthesia of Th l0 dermatomes, difficulty in defecating, and urinary retention. Magnetic resonance (MR) T2-weighted images showed a high-signal lesion in the center of the medulla oblongata, patchy high-signal lesions throughout the spinal cord, and swelling of the cervical spinal cord. A polymerase chain reaction test for EBV DNA in the CSF was positive. After treatment with high-dose methyl-predonisolone, the neurological symptoms improved rapidly and the high-signal lesions in the spinal cord improved. EBV DNA in the CSF was not detected after treatment with ganciclovir. This case suggests that steroid and ganciclovir are effective for the treatment of EBV-related encephalomyelitis.

[Antispasm therapy using combination of midazolam and propofol for severe tetanus].

A 68-year-old healthy woman without any evidence of recent wound, developed nuchal pain, difficulty in swallowing and trisumus in 10 days. Because of respiratory failure due to generalized muscle spasm, she was intubated and required mechanical ventilation. Midazolam was administered as an antispastic therapy followed by human tetanus immune globulin and tetanus toxoid. Propofol was added on 9 days after intubation, since muscle spasm such as opisthotonus or respiratory spasm did not improve under midazolam and intermittent administration of vecuronium. Thereafter, her muscle spasm and hypertensive response were well controlled. The authors suggested that a combined use of midazolam and propofol was an optional antispastic therapy in patients with severe tetanus.