Na+/Ca2+ exchange activity is increased in Alzheimer's disease brain tissues

Colvin, Robert A.; Bennett, Jonathan P.; Colvin, Sharon L.; Allen, Richard A.; Martínez, John W.; Miner, Gary

doi:10.1016/0006-8993(91)91056-7

Cited by 40 publications

(20 citation statements)

References 33 publications

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“…We had also reported that CT 105 inhibited calcium uptake into rat brain microsomes by Mg 2ϩ -Ca 2ϩ ATPase (51) and that CT 105 inhibits the activity of Na ϩ -Ca 2ϩ exchanger in SK-N-SH cells (52). Alterations in neuronal Na ϩ -Ca 2ϩ exchange in AD have been reported (53).…”

Section: Discussionmentioning

confidence: 90%

Carboxyl‐terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity

Kim

Park

et al. 2000

FASEB j.

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Numerous lines of evidence indicate that some of the neurotoxicity associated with Alzheimer's disease (AD) is due to proteolytic fragments of the amyloid precursor protein (APP). Most research has focused on the amyloid beta peptide (Abeta). However, the possible role of other cleaved products of APP is less clear. We have previously shown that a recombinant carboxy-terminal 105 amino acid fragment (CT 105) of APP induced strong nonselective inward currents in Xenopus oocyte; it also revealed neurotoxicity in PC12 cells and primary cortical neurons, blocked later phase of long-term potentiation in rat hippocampus in vivo, and induced memory deficits and neuropathological changes in mice. We report here that the pretreatment with CT 105 for 24 h at a 10 microM concentration increases intracellular calcium concentration by about twofold in SK-N-SH and PC 12 cells, but not in U251 cells, originated from human glioblastoma. In addition, the calcium increase and toxicity induced by CT 105 were reduced by cholesterol and MK 801 in SK-N-SH and PC 12 cells, whereas the toxicity of Abeta(1-42) was attenuated by nifedipine and verapamil. CT 105 rendered SK-N-SH cells and rat primary cortical neurons more vulnerable to glutamate-induced excitotoxicity. Also, conformational studies using circular dichroism experiments showed that CT 105 has approximately 15% of beta-sheet content in phosphate buffer and aqueous 2,2, 2-trifluoroethanol solutions. However, the content of beta-sheet conformation in dodecyl phosphocholine micelle or in the negatively charged vesicles, is increased to 22%-23%. The results of this study showed that CT 105 disrupts calcium homeostasis and renders neuronal cells more vulnerable to glutamate-induced excitotoxicity, and that some portion of CT 105 has partial beta-sheet conformation in various environments, which may be related to the self-aggregation and toxicity. This may be significantly possibly involved in inducing the neurotoxicity characteristic of AD.

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Section: Discussionmentioning

confidence: 90%

Carboxyl‐terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity

Kim

Park

et al. 2000

FASEB j.

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“…In this regard, it is generally assumed that decreased brain CO activity is an established feature of AD. Analysis of all of the available postmortem brain data (Colvin et al, 1991 ; Cooper et al, 1993 ; Reichmann et al, 1993 ; Simonian and Hyman, 1993 ; Parker et al, 1994 ; Mutisya et al, 1994 ; Cavelier et al, 1995 ; Chagnon et al, 1995 ; Parker and Parks, 1995 ; Maurer et al, 1995 ; Wong‐Riley et al, 1997), including those of our original report (Kish et al, 1992), however, indicates that no consensus has yet been reached on either the magnitude of the brain enzyme activity reduction in AD (ranging from no statistically significant change to a near‐total decrease) or the areas of brain affected (selective loss in specific cerebral cortical regions versus generalized reduction throughout all cortical/subcortical brain areas) (for extensive review, see Kish, 1997). Similarly, although decreased CO mRNA has been reported in several brain areas of patients with AD, the issue as to whether these changes are restricted to regions of neuronal pathology (Chandrasekaran et al, 1994, 1997) or represent a global phenomenon (Simonian and Hyman, 1994) has not yet been resolved.…”

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confidence: 99%

Decreased Brain Protein Levels of Cytochrome Oxidase Subunits in Alzheimer's Disease and in Hereditary Spinocerebella Ataxia Disorders

Kish¹,

Mastrogiacomo²,

Guttman³

et al. 1999

Journal of Neurochemistry

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Abstract:Controversy exists as to the clinical importance, cause, and disease specificity of the cytochrome oxidase (CO) activity reduction observed in some patients with Alzheimer's disease (AD). Although it is assumed that the enzyme is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subunits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, groups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrations of all four CO subunits were significantly decreased (Ϫ19 to Ϫ47%) in temporal and parietal cortices in the AD group but were not significantly reduced (Ϫ12 to Ϫ17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (Ϫ42 to Ϫ47%) generally exceeded that encoded by nuclear DNA (Ϫ19 to Ϫ43%). In the spinocerebellar ataxia disorders, COX I and COX II levels were significantly decreased in cerebellar cortex (Ϫ22 to Ϫ32%) but were normal or close to normal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial-and nuclear-encoded CO subunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodegenerative process. Key Words: Cytochrome oxidase-Complex IV-Alzheimer's disease-Spinocerebellar ataxia type I-Friedreich's ataxia-Mitochondria-Oxidative phosphorylation. J. Neurochem. 72, 700 -707 (1999).Since Parker et al.'s biochemical study (1990) in platelets of patients with Alzheimer's disease (AD), much attention continues to be devoted to the possibility that the fundamental cause of this disease, in the majority of patients with the disorder, is a defect in the key mitochondrial electron transport chain enzyme cytochrome oxidase (CO; for review, see Parker and Davis, 1997). This notion is particularly attractive as in vitro data indicate that a CO defect could alter processing of the ␤-amyloid precursor protein (Gabuzda et al., 1994). However, most aspects of this issue still remain controversial. In this regard, it is generally assumed that decreased brain CO activity is an established feature of AD. Analysis of all of the available postmortem brain data (Colvin et al., 1991;Cooper et al., 1993;Reichmann et al., 1993;Simonian and Hyman, 1993;Parker et al., 1994;Mutisya et al., 1994;Cavelier et al., 1995;Chagnon et al., 1995;Parker and Parks, 1995;Maurer et al., 1995;Wong-Riley et al., 1997), including those of our original report...

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“…In many cell types from AD tissues, including fibroblasts, changes have been demonstrated in signal transduction systems (5) that involve calcium homeostasis (6)(7)(8)(9), ion channel permeability (10)(11)(12), cyclic AMP (13,14), and phosphoinositide metabolites (15). Altered production of ␤AP also has been shown (16)(17)(18).…”

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confidence: 99%

Alzheimer’s-specific effects of soluble β-amyloid on protein kinase C-α and -γ degradation in human fibroblasts

Favit

Grimaldi

Nelson

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Na+/Ca2+ exchange activity is increased in Alzheimer's disease brain tissues

Cited by 40 publications

References 33 publications

Carboxyl‐terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity

Carboxyl‐terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity

Decreased Brain Protein Levels of Cytochrome Oxidase Subunits in Alzheimer's Disease and in Hereditary Spinocerebella Ataxia Disorders

Alzheimer’s-specific effects of soluble β-amyloid on protein kinase C-α and -γ degradation in human fibroblasts

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