amyloid, glutathione, gender, autism

[Guest guest]

Amyloid & autism (3-4).

Amyloid, glutathione, and gender (1-2).

Glutathione and autism (eg, 5-7).

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1. Gender differences in glutathione metabolism in Alzheimer's disease.

<http://www.ncbi.nlm.nih.gov/pubmed/15693022>

Liu H, Harrell LE, Shenvi S, Hagen T, Liu RM.

J Neurosci Res. 2005 Mar 15;79(6):861-7.

The mechanism underlying Alzheimer's disease (AD), an age-related

neurodegenerative disease, is still an area of significant controversy.

Oxidative damage of macromolecules has been suggested to play an

important role in the development of AD; however, the underlying

mechanism is still unclear. In this study, we showed that the

concentration of glutathione (GSH), the most abundant intracellular free

thiol and an important antioxidant, was decreased in red blood cells

from male AD patients compared with age- and gender-matched controls.

However, there was no difference in blood GSH concentration between the

female patients and female controls. The decrease in GSH content in red

blood cells from male AD patients was associated with reduced activities

of glutamate cysteine ligase and glutathione synthase, the two enzymes

involved in de novo GSH synthesis, with no change in the amount of

oxidized glutathione or the activity of glutathione reductase,

suggesting that a decreased de novo GSH synthetic capacity is

responsible for the decline in GSH content in AD. These results showed

for the first time that GSH metabolism was regulated differently in male

and female AD patients.

2. Role of glutathione in intracellular amyloid-alpha precursor

protein/carboxy-terminal fragment aggregation and associated

cytotoxicity. <http://www.ncbi.nlm.nih.gov/pubmed/15857408>

Woltjer RL, Nghiem W, Maezawa I, Milatovic D, Vaisar T, Montine KS,

Montine TJ.

J Neurochem. 2005 May;93(4):1047-56.

Abstract Alterations in glutathione (GSH) metabolism are associated with

neurodegeneration in Alzheimer's disease (AD), and GSH depletion follows

application of exogenous fibrillar amyloid beta (Abeta) peptides in

experimental systems; these results are commonly cited as evidence of

oxidative damage in AD. We used MC65 human neuroblastoma cells that

conditionally express carboxy-terminal fragments of the Abeta precursor

protein (Abeta/CTFs) to directly test the hypothesis that GSH is part of

the cellular response to stressors associated with Abeta/CTF

accumulation and not simply a marker of oxidative damage. Our data

showed that Abeta/CTFs accumulated by post-translational processes and

were associated with progressive increases in oxidative damage and

cytotoxicity. Ethycrinic acid (EA) or diethyl maleate (DEM), reagents

that deplete GSH through non-specific thiol adduction, gave rise to

dose-dependent cytotoxicity that was independent of Abeta/CTF expression

and minimally responsive to alpha-tocopherol (AT). In contrast,

buthionine sulfoximine (BSO), a selective inhibitor of GSH synthase, not

only augmented Abeta/CTF-associated cell death but unexpectedly

potentiated Abeta/CTF accumulation; both outcomes were completely

suppressed by AT. These data suggest that antioxidants may serve as

'Abeta targeting' therapies that suppress toxic protein aggregation

rather than simply acting as downstream radical scavengers.

3. High levels of Alzheimer beta-amyloid precursor protein (APP) in

children with severely autistic behavior and aggression.

<http://www.ncbi.nlm.nih.gov/pubmed/16948926>

Sokol DK, Chen D, Farlow MR, Dunn DW, Maloney B, Zimmer JA, Lahiri DK.

J Child Neurol. 2006 Jun;21(6):444-9.

4. Peripheral biomarkers in Autism: secreted amyloid precursor

protein-alpha as a probable key player in early diagnosis.

<http://www.ncbi.nlm.nih.gov/pubmed/19079679>

AR, Giunta BN, Obregon D, Nikolic WV, Tian J, Sanberg CD, Sutton

DT, Tan J.

Int J Clin Exp Med. 2008;1(4):338-44.

5. Cellular and mitochondrial glutathione redox imbalance in

lymphoblastoid cells derived from children with autism.

<http://www.ncbi.nlm.nih.gov/pubmed/19307255>

SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW.

FASEB J. 2009 Aug;23(8):2374-83.

6. The severity of autism is associated with toxic metal body burden and

red blood cell glutathione levels.

<http://www.ncbi.nlm.nih.gov/pubmed/20107587>

JB, Baral M, Geis E, J, Ingram J, Hensley A, Zappia I,

Newmark S, Gehn E, Rubin RA, K, Bradstreet J, El-Dahr JM.

J Toxicol. 2009;2009:532640. Epub 2009 Aug 26.

7. Evaluation of Oxidative Stress in Autism: Defective Antioxidant

Enzymes and Increased Lipid Peroxidation.

<http://www.ncbi.nlm.nih.gov/pubmed/20845086>

Meguid NA, Dardir AA, Abdel-Raouf ER, Hashish A.

Biol Trace Elem Res. 2010 Sep 16. [Epub ahead of print]

Autism is a neurodevelopmental disorder of childhood with poorly

understood etiology and pathology. This pilot study aims to evaluate the

levels of antioxidant enzymes, superoxide dismutase (SOD) and

glutathione peroxidase (GSH-Px), and levels of malondialdehyde (MDA), a

marker of lipid peroxidation, in Egyptian autistic children. Autism is a

neurodevelopmental disorder of childhood with poorly understood etiology

and pathology. The present study included 20 children with autism

diagnosed by DSM-IV-TR criteria and Childhood Autism Rating Scale.

Controls included 25 age-matched healthy children. Cases were referred

to Outpatient Clinic of Children with Special Needs Department, National

Research Center, Cairo, Egypt. We compared levels of SOD, GSH-Px, and

MDA in children with autism and controls. In children less than 6 years

of age, levels of SOD, and GSH-Px were significantly lower in autistic

children compared with their controls, while MDA was significantly

higher among patients than controls. In children older than 6 years,

there was no significant difference in any of these values between cases

and controls. We concluded that children with autism are more vulnerable

to oxidative stress in the form of increased lipid peroxidation and

deficient antioxidant defense mechanism especially at younger children.

We highlight that autistic children might benefit from antioxidants

supplementation coupled with polyunsaturated fatty acids. Moreover,

early assessment of antioxidant status would have better prognosis as it

may decrease the oxidative stress before inducing more irreversible

brain damage.