No abstract

No abstract

To investigate the possibility that mitochondrial oxidative damage or oxidative DNA damage or both contribute to the neurodegenerative process of sporadic amyotrophic lateral sclerosis (sALS), this study used high-performance liquid chromatography with an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q10 (CoQ10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 17 patients with sALS and 17 age-matched controls with no neurological diseases. The percentage of oxidized CoQ10 in the CSF of sALS patients was greater than that in the CSF of controls (p<0.002) and was negatively correlated with the duration of illness (rho=-0.61, p<0.01). The concentration of 8-OHdG in the CSF of sALS patients was greater than that in the CSF of controls (p<0.005) and was positively correlated with the duration of illness (rho=0.53, p<0.005). The percentage of oxidized CoQ10 was correlated with the concentrations of 8-OHdG in the CSF of sALS patients (rho=-0.53, p<0.05). These results suggest that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of sporadic amyotrophic lateral sclerosis.

A quantitative assessment using DKI and QSM analyses, particularly MK-dMPR and MS-PUp values, can readily identify patients with parkinsonism.

Apolipoprotein E (apoE) ⑀4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid ␤-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.It has been shown that the possession of the apolipoprotein E (apoE) ⑀4 allele is a major risk factor for Alzheimer disease (AD) 2 (1). In the central nervous system, apoE is one of the major lipid acceptors to remove cholesterol from cells and generate HDL particles. Previous studies have shown that apoE isoforms do not affect apoE binding to ABCA1, that apoE-mediated ABCA1-dependent cholesterol efflux is not affected by apoE isoforms in fibroblasts (2), and that there is no apoE-isoform-dependence on apoE-mediated lipid efflux from mouse astrocytes (3). Other lines of evidence have shown that apoE induces lipid efflux from macrophages and neural cells in an isoform-dependent manner; apoE3 induces a greater lipid efflux than apoE4 (4 -9). It has been shown that two major factors cause this apoE-isoform-dependent generation of HDL. Namely, intramolecular domain interaction occurring in apoE4 attenuates apoE4 ability to generate HDL and intermolecular dimerization by disulfide bonds between cysteines in apoE3 enhances apoE3 ability to generate HDL in neural cells (10).Recent studies have shown other functions of apoE as well, including an intracellular function of apoE (11, 12) and a function of apoE in clearance and degradation of A␤. It has been demonstrated that apoE isoforms differentially regulate A␤ clearance from the brain (13), and that an increased level of lipidated apoE, namely, apoE-HDL, stimulates A␤ degradation (14). These lines of evidence suggest that the lower ability of apoE4 than apoE3 to generate HDL would result in an enhanced A␤ deposition in the brain owing to the lower A␤ degradation/clearance from the brain. Similarly, apoE-isoform-dependent HDL generation results in a lower HDL-cholesterol level in serum in those who possess apoE ⑀4 allele, which is a risk factor for atherosclerosis (15) and cerebral infarction (16).In light of these findings, it is interesting t...