Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology

Abstract

Recent reports have suggested that mitochondrial dysfunction may contribute to the progression of the pathology of Alzheimer's disease (AD). However, both increases and decreases in the activity of cytochrome oxidase have been described in the hippocampi of AD patients. In this study we used immunohistochemistry and quantitative autoradiographic methods to study the expression pattern of two cytochrome oxidase subunit proteins (nuclear-encoded COX IV and mitochondrial-encoded COX I) in the hippocampus in relation to the development of AD-type pathology. We found heterogeneous expression of both COX subunits in AD with an increased expression of both subunit proteins in healthy, non-tangle-bearing, neurones but absence of both subunit proteins in tangle-bearing neurones. Levels of COX IV but not of COX I were related to the amount of hyperphosphorylated tau accumulated in the same hippocampal region but not to the amount of amyloid deposited in sporadic AD. In Down's syndrome COX I and COX IV were similarly increased in the presence of AD pathology in non-tangle-bearing neurones. However, in these cases levels of enzyme expression were correlated to the amount of amyloid accumulation but not the amount of hyperphosphorylated tau in the hippocampus. We believe that heterogeneity of expression of mitochondrial enzyme proteins between neurones may contribute to the conflicting conclusions in previous reports regarding relative levels of cytochrome oxidase activity in the hippocampus in AD. We hypothesise that the increased mitochondrial enzyme expression in healthy-appearing neurones of AD brains may represent a physiological response to increased functional demand on surviving neurones as a consequence of AD-related neuronal pathology.

Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease

“…Increased MtDNA damage and reduced MtDNA content in AD were associated with reduced expression of mitochondrial protein and COX, and reduced MitoTracker Green labeling. Although reduced COX expression in AD has been reported previously (Chandrasekaran et al, 1998;Nagy et al, 1999;Wong-Riley et al, 1997), the present study provides new information indicating that in AD, impaired mitochondrial function with reduced expression of mitochondriaencoded genes is likely caused by MtDNA damage. In addition, enhanced MtDNA damage results in reduced mitochondrial mass (mitochondrial protein expression, MitoTracker Green labeling) and reduced MtDNA content.…”

“…de la Monte et al tions (Nagy et al, 1999). One possible explanation for the paradoxically increased mitochondrial mass (abundance), mitochondrial gene expression, and MtDNA content observed in small populations of AD brain neurons is that, during the early stages of MtDNA damage, cellular responses can include compensatory proliferation of mitochondria.…”

Preventing Alzheimer's disease by means of natural selection

“…It stands to reason that neurons with the highest energy demands will be the most affected by age-related mitochondrial dysfunction, and there is evidence that affected neurons attempt to increase their respiratory capacity. Immunofluorescence studies suggest that the sub-population of neurons affected by mitochondrial abnormalities and oxidative damage overexpress cytochrome oxidase to compensate for energetic insufficiencies [72][73][74]. Another mechanism for adapting to bioenergetic stress is the cycle of mitochondrial fusion, fission and mitophagy that helps to increase both the number and quality of mitochondria [25,75].…”

Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication

“…Structurally abnormal mitochondria have been observed in AD brains (3,4), and deficiencies in mitochondrial OXPHOS enzymes, such as cytochrome c oxidase (COX or complex IV), have been repeatedly reported in the brains and other tissues of AD patients (5,6). Moreover, mitochondrial OXPHOS defects have been recovered in cultured human cell cybrids by fusion of AD patient blood platelets to human cell lines that lack mtDNA ( o cells) (5)(6)(7)(8)(9)(10)(11)(12)(13).…”