Alzheimer’s Pathogenesis and Its Link to the Mitochondrion

Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD and reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionisation tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay.AD patients (n=21) and healthy age-matched control subjects (n=16) were supplemented with either Macushield™ (10 mg meso-zeaxanthin, 10 mg lutein, 2 mg zeaxanthin) or placebo (sunflower oil) for six months.The MRM-MS method determined serum POVPC sensitively (from 10 µl serum) and reproducibly (CV=7.9%). At baseline, AD subjects had higher serum POVPC compared to age-matched controls, (p=0.017) and cognitive function was correlated inversely with POVPC (r=−0.37; p=0.04). After six months of carotenoid intervention, serum POVPC was not different in AD patients compared to healthy controls. However, POVPC was significantly higher in control subjects after six months of carotenoid intervention compared to their baseline (p=0.03). Serum IsoP concentration was unrelated to disease or supplementation. Serum FRAP was significantly lower in AD than healthy controls but was unchanged by carotenoid intervention (p=0.003).In conclusion, serum POVPC is higher in AD patients compared to control subjects, is not reduced by carotenoid supplementation and correlates with cognitive function.

show abstract

“…Cognitive decline begins before appearance of the dementia syndrome [1], [2] and shares common features with AD and the ageing brain [2].…”

Section: Introductionmentioning

confidence: 99%

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Ademowo

Dias

Milic

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…To date, mitochondrial respiratory failure and oxidative stress can contribute to cognitive decline (Simoncini et al 2015). It has been reported that MELAS patients without stroke-like episodes can also develop cognitive decline (Finsterer 2009).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that MELAS patients without stroke-like episodes can also develop cognitive decline (Finsterer 2009). The accumulation of somatic mitochondrial DNA mutations accelerates oxidative damage, increases the production of reactive oxygen species, and promotes amyloid accumulation (Simoncini et al 2015). Moreover, recent studies have shown that diabetes itself could be a risk factor for cognitive decline, and a history of severe hypoglycemia is associated with a greater risk of cognitive decline (Whitmer et al 2009;Gudala et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes

Murakami

Shinoto

Yonemitsu

et al. 2016

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients.

show abstract

“…The bioenergy production phenotype of cells can be reprogrammed in response to a variety of stimuli and perturbations5. Dysfunction of mitochondria, which produce bioenergy in form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), has been associated with a variety of neurodegenerative diseases, including Alzheimer’s67 and Parkinson’s8. Similarly, alteration in energy metabolism manifested as an upregulation of oxidative glycolysis in cancer cells (Warburg effect) has been recognized as one of the hallmarks of cancer9.…”

mentioning

confidence: 99%

A platform for high-throughput bioenergy production phenotype characterization in single cells

Kelbauskas

Glenn

Anderson

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Driven by an increasing number of studies demonstrating its relevance to a broad variety of disease states, the bioenergy production phenotype has been widely characterized at the bulk sample level. Its cell-to-cell variability, a key player associated with cancer cell survival and recurrence, however, remains poorly understood due to ensemble averaging of the current approaches. We present a technology platform for performing oxygen consumption and extracellular acidification measurements of several hundreds to 1,000 individual cells per assay, while offering simultaneous analysis of cellular communication effects on the energy production phenotype. The platform comprises two major components: a tandem optical sensor for combined oxygen and pH detection, and a microwell device for isolation and analysis of single and few cells in hermetically sealed sub-nanoliter chambers. Our approach revealed subpopulations of cells with aberrant energy production profiles and enables determination of cellular response variability to electron transfer chain inhibitors and ion uncouplers.

show abstract

Alzheimer’s Pathogenesis and Its Link to the Mitochondrion

Cited by 32 publications

References 98 publications

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes

A platform for high-throughput bioenergy production phenotype characterization in single cells

Contact Info

Product

Resources

About