Altered hexokinase activity in skin cultured fibroblasts and leukocytes from Alzheimer's disease patients

Sorbi, Sandro; Mortilla, M.; Piacentini, Silvia; Tonini, Stefano; Amaducci, L.

doi:10.1016/0304-3940(90)90138-y

Cited by 25 publications

(14 citation statements)

References 10 publications

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“…Our findings are in accordance with the findings of Mortilla and Sorbi [28] and Pomara et al [9], who used clinical and methodological criteria identi cal to our study. Our data however are in contrast with the results of Sorbi et al [23], who reported a decreased HK activity in familial AD leukocytes and fibroblasts. The difference is likely due to a difference in Sorbi's definition of familial AD (autosomal dominant) which differs from ours (affected first-degree relative).…”

Section: Discussioncontrasting

confidence: 57%

“…Other authors have reported but not commented on this trend. The study of Pomara et al [9] of HK in lymphocytes of AD patients as well as the work of Sorbi et al [23] in fibroblasts and leukocytes found a similar pattern where the AD group averaged a SD 42% higher than controls. This trend was also present when HK was measured in brain tissue [21], The cause of higher HK activity and larger variance in the old and AD is unclear.…”

Section: Discussionmentioning

confidence: 63%

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Leukocyte Hexokinase Activity in Aging and Alzheimer Disease

Antuono

Ravanelli-Meyer²,

Nicholson³

et al. 1995

Dement Geriatr Cogn Disord

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We determined the effects of clinical variables on hexokinase (HK) activity in leukocytes from Alzheimer''s disease (AD) patients and controls. Age accounted for 51% of the variance in HK activity in the young and 23% in the old. Duration of illness in both familial and sporadic AD accounted for HK levels by 32 and 38%, respectively. Hexokinase activity increases with age and does not discriminate between familial and sporadic AD.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 63%

Leukocyte Hexokinase Activity in Aging and Alzheimer Disease

Antuono

Ravanelli-Meyer²,

Nicholson³

et al. 1995

Dement Geriatr Cogn Disord

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“…Hexokinase interaction with the mitochondrial VDAC also plays an important role in preventing mitochondria-mediated apoptosis and promoting cell survival in neurons and other cell types [52]–[54]. AD patients exhibit declined hexokinase activity in the brain, cerebral microvessel, leukocytes and fibroblasts [55]–[57]. Previous studies have demonstrated that ovarian hormone loss led to compromised-brain hexokinase activity, whereas short-term estrogen treatment was efficacious to increase hexokinase activity in rat brains [12].…”

Section: Discussionmentioning

confidence: 99%

Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's

et al. 2013

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Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[18F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.

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“…Type II hexokinasemitochondrial interactions were observed to promote tumor cell growth, and hexokinase has been suggested as the ideal target for therapeutic intervention (4,5). Modifications in the catalytic activity of hexokinase have been suggested to play a role in the pathogenesis of the Alzheimer's disease (6). Recently, it has been shown that hexokinase plays a role in sensing and maintaining the glucose levels and in signal transduction to regulate the expression of genes in plants (7,8).…”

mentioning

confidence: 99%

Effect of pH on the Stability and Structure of Yeast Hexokinase A

Kumar

Tiwari

Bhat

2004

Journal of Biological Chemistry

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pH and salts have a marked effect on the stability, structure, and function of many globular proteins due to their ability to influence the electrostatic interactions. In this work, calorimetry, CD, and fluorescence studies have been carried out to understand the pH-dependent conformational changes of the two-domain protein yeast hexokinase A. In conjunction with the crystal structural data available, the present results have enabled the complete characterization and analysis of the pH-dependent conformational changes of the enzyme that have strong implications in understanding its structure-function relationship. The calorimetric profiles show a single thermal transition in the acidic pH range, whereas two independent transitions were observed in the alkaline pH range, suggesting the structural merger of the domains at the acidic pH. Comparison of the thermal transitions at pH 8.5 studied by different techniques suggests that the first transition corresponds to the smaller domain, and the second transition corresponds to the larger domain. The acid-denatured state of hexokinase A has high secondary structure content with little or no tertiary interactions and binds to the hydrophobic dye 8-anilinonaphthalene-1-sulfonic acid, suggesting that it is a molten globule-like state, whereas the alkali-denatured state is less structured than the acid-denatured state but more structured than the urea-denatured state, suggestive of a premolten globule-like state. Structural analysis using the published hexokinase B structure as well as the hexokinase A structure with the revised amino acid sequence in conjunction with the results obtained by us suggests that the ionization state of the acidic residues at the active site could regulate domain movements that are responsible for the opening and the closure of the cleft between the two domains and in turn affect the structure and function of the enzyme.

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Altered hexokinase activity in skin cultured fibroblasts and leukocytes from Alzheimer's disease patients

Cited by 25 publications

References 10 publications

Leukocyte Hexokinase Activity in Aging and Alzheimer Disease

Leukocyte Hexokinase Activity in Aging and Alzheimer Disease

Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's

Effect of pH on the Stability and Structure of Yeast Hexokinase A

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