Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease

Abstract

Considerable data support the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions, such as cell redox states and acute versus chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of mitochondrial deficits and a reduction in oxidative stress will reduce clinical and pathological changes and benefit patients.

Fig. 1

Activities of TCA cycle enzymes change in brains of patients with AD. Activities of PDHC and all of the TCA cycle enzymes were measured in autopsied brains from patients with AD. Data are expressed as percent of control.

Fig. 2

GSSG appears to glutathionylate KGDHC. Purified KGDHC was incubated with GSSG. The samples were run on SDS-PAGE and probed with antibodies to each of the three components of KGDHC and to glutathione. The immunoreactive bands clearly overlapped. Analagous results were obtained with GSH.

Fig. 3

Fig. 4

Diminished E2k in HEK cells increases the H₂O₂ induced ROS and cell death. Cells with various levels of E2k protein subunits were utilized. KGDHC activity declined in the cells with about a 50 percent reduction but returned to normal in the lines with the lowest levels of E2k. The cells were incubated with H₂O₂ and cell death and fluorescence were determined.

Fig. 5

E2k modifies the response of MDH activity and message to oxidants. Cells with varying levels of the E2k subunit of KGDHC were incubated with H₂O₂ and the response of MDH activitity and message levels were determined.

Fig. 6

Thiamine deficiency accelerates accumulation of compact plaques. Mice that were plaque competent but did not yet have plaques were made thiamine deficient for 10 days. APP processing was altered and plaque accumulation was accelerated.

Fig. 7

Trolox diminishes H₂O₂-induced ROS but does not protect KGDHC. Cells were incubated with concentrations of Trolox that diminished H₂O₂ induced increases in cDCF. These concentrations of Trolox did not protect KGDHC from H₂O₂

Fig. 8

KMV diminishes bombesin-releasable calcium stores (BRCS) in oxidant treated fibroblasts and in AD fibroblasts. H₂O₂ increases BRCS. The increases can be diminished by KMV. The AD related increases in BRCS can also be diminished by KMV. Bars with different symbols are significantly different from each other.