Accumulation of Exogenous Amyloid-<i>Beta</i>Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

Rosales-Corral, Sergio; Acuña-Castroviejo, Darı́o; Tan, Dun Xian; López-Armas, Gabriela del Carmen; Cruz-Ramos, José Alfonso; Munoz, Ruben; Melnikov, Valery; Manchester, Lucien C.; Reíter, Russel J.

doi:10.1155/2012/843649

Cited by 56 publications

(49 citation statements)

References 98 publications

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“…4, 5). These data are in agreement with recent studies indicating that loss of serotonergic neurons correlates with AD severity, memory impairment, and neuropsychiatric symptoms [42], [46], and that melatonin protects against Aβ toxicity in cellular and animals models of AD [47], [48]. Additional significant changes in neurotransmitter metabolism were observed in the acetylcholine pathway in CSF from AD individuals and in gamma amino butyric acid (GABA) pathway in plasma from MCI patients (Fig.…”

Section: Discussionsupporting

confidence: 92%

Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

et al. 2013

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Alzheimer’s Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.

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Section: Discussionsupporting

confidence: 92%

Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

et al. 2013

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“…Recently, Melatonin showed protection against exogenous β -amyloid deposition induced mitochondrial dysfunction and other neurodegenerative disease models [39–41]. Further, earlier publication from this lab also demonstrated that melatonin protects memory impairments in rats [42, 43].…”

Section: Introductionmentioning

confidence: 99%

Standardized Extract ofBacopa monnieraAttenuates Okadaic Acid Induced Memory Dysfunction in Rats: Effect on Nrf2 Pathway

Dwivedi

Nagarajan²,

Hanif³

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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The aim of the present study is to investigate the effect of standardized extract of Bacopa monnieri (memory enhancer) and Melatonin (an antioxidant) on nuclear factor erythroid 2 related factor 2 (Nrf2) pathway in Okadaic acid induced memory impaired rats. OKA (200 ng) was administered intracerebroventricularly (ICV) to induce memory impairment in rats. Bacopa monnieri (BM-40 and 80 mg/kg) and Melatonin (20 mg/kg) were administered 1 hr before OKA injection and continued daily up to day 13. Memory functions were assessed by Morris water maze test on days 13–15. Rats were sacrificed for biochemical estimations of oxidative stress, neuroinflammation, apoptosis, and molecular studies of Nrf2, HO1, and GCLC expressions in cerebral cortex and hippocampus brain regions. OKA caused a significant memory deficit with oxidative stress, neuroinflammation, and neuronal loss which was concomitant with attenuated expression of Nrf2, HO1, and GCLC. Treatment with BM and Melatonin significantly improved memory dysfunction in OKA rats as shown by decreased latency time and path length. The treatments also restored Nrf2, HO1, and GCLC expressions and decreased oxidative stress, neuroinflammation, and neuronal loss. Thus strengthening the endogenous defense through Nrf2 modulation plays a key role in the protective effect of BM and Melatonin in OKA induced memory impairment in rats.

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“…34 sCD44 internalization may involve mitochondrial dysfunction in a fashion similar to that of b-amyloid fragments, 35,36 causing abnormal mitochondrial function and cell death. The extent of exogenous b-amyloid co-localization in mitochondria is variable from partial without quantification [36][37][38] and 1% to 9%. 39 sCD44 is released by proteolytic cleavage 40 (shedding) from membrane-anchored CD44, which influences CD44-mediated HA binding to cell surfaces.…”

Section: Discussionmentioning

confidence: 99%

sCD44 Internalization in Human Trabecular Meshwork Cells

Nolan

Koga

Walker

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine whether soluble CD44 (sCD44), a likely biomarker of primary open-angle glaucoma (POAG), is internalized in cultured human trabecular meshwork (TM) cells and trafficked to mitochondria. METHODS.In vitro, 32-kD sCD44 was isolated from human sera, biotinylated, and dephosphorylated. TM cells were incubated for 1 hour at 48C with biotinylated albumin (b-albumin), biotinlabeled sCD44 (b-sCD44), or hypophosphorylated biotinlabeled sCD44 (-p b-sCD44) in the presence or absence of unlabeled sCD44, hyaluronic acid (HA), and a selected 10-mer HA binding peptide. The slides were warmed for 1 or 2 hours at 378C, and 125 nM MitoTracker Red was added for the last 20 minutes of the incubation. The cells were washed, fixed, incubated with anti-biotin antibody and FITC-labeled goat antimouse antibody, and examined under a confocal microscope.RESULTS. TM cell membranes were positive for b-sCD44 after 48C incubation. When the temperature was raised to 378C, bsCD44 or -p b-sCD44 appeared in the cytoplasm. The internalization of b-sCD44 was blocked by excess unlabeled sCD44, HA, and a 10-mer HA-binding peptide. Double label experiments with b-sCD44 or -p b-sCD44 and MitoTracker Red indicated partial overlap. The percent co-localization of MitoTracker Red at 2 hours and FITC -p b-sCD44 was 17.4% (P < 0.001) and for FITC b-sCD44 was 11.7% (P < 0.001) compared with b-albumin. The influence of putative CD44 phosphorylation sites on mitochondrial trafficking was determined by TargetP 1.1.CONCLUSIONS. sCD44 is internalized by TM cells and trafficked in part to mitochondria, which may be a factor in the toxicity of sCD44 in the POAG disease process. (Invest Ophthalmol Vis Sci. 2013;54:592-601)

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Accumulation of Exogenous Amyloid-BetaPeptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

Cited by 56 publications

References 98 publications

Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

Standardized Extract ofBacopa monnieraAttenuates Okadaic Acid Induced Memory Dysfunction in Rats: Effect on Nrf2 Pathway

sCD44 Internalization in Human Trabecular Meshwork Cells

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