Homocysteine potentiates β‐amyloid neurotoxicity: role of oxidative stress

Ho, Pei I.; Collins, Scott C.; Dhitavat, Sirikarnt; Ortiz, Daniela; Ashline, David J.; Rogers, Eugene; Shea, Thomas B.

doi:10.1046/j.1471-4159.2001.00384.x

Cited by 260 publications

(180 citation statements)

References 39 publications

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“…Hcy induces accumulation of reactive oxygen species (ROS) and stimulates neurotoxicity [43,44] , whereas H 2 S scavenges ROS and protects neurons against oxidative stress [45][46][47][48] . Furthermore, both elevation of Hcy and decrease of H 2 S are detected in the brains of AD patients [49] .…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Wei

et al. 2014

Acta Pharmacol Sin

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Aim: Homocysteine (Hcy) can elicit neuronal cell death, and hyperhomocysteinemia is a strong independent risk factor for Alzheimer's disease. The aim of this study was to examine the effects of hydrogen sulfide (H 2 S) on Hcy-induced endoplasmic reticulum (ER) stress and neuronal apoptosis in rat hippocampus. Methods: Adult male SD rats were intracerebroventricularly (icv) injected with Hcy (0.6 μmol/d) for 7 d. Before Hcy injection, the rats were treated with NaHS (30 or 100 μmol·kg -1 ·d -1 , ip) and/or k252a (1 μg/d, icv) for 2 d. The apoptotic neurons were detected in hippocampal coronal slices with TUNEL staining. The expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and BDNF in the hippocampus were examined using Western blotting assays. The generation of H 2 S in the hippocampus was measured with the NNDPD method. Results: Hcy markedly inhibited the production of endogenous H 2 S and increased apoptotic neurons in the hippocampus. Furthermore, Hcy induced ER stress responses in the hippocampus, as indicated by the upregulation of GRP78, CHOP, and cleaved caspase-12. Treatment with the H 2 S donor NaHS increased the endogenous H 2 S production and BDNF expression in a dosedependent manner, and significantly reduced Hcy-induced neuronal apoptosis and ER stress responses in the hippocampus. Treatment with k252a, a specific inhibitor of TrkB (the receptor of BDNF), abolished the protective effects of NaHS against Hcy-induced ER stress in the hippocampus. Conclusion: H 2 S attenuates ER stress and neuronal apoptosis in the hippocampus of Hcy-treated rats via upregulating the BDNF-TrkB pathway.

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Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Wei

et al. 2014

Acta Pharmacol Sin

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“…In addition, Hcy potentiates Ab-induced neurodegeneration affecting cytosolic calcium. 46 Thus, formation of Fg-Ab complex during HHcy has deleterious effect in brain. Previously, we have shown that an acute injection of Hcy and the resultant elevation of its blood content caused cerebrovascular protein leakage in mice.…”

Section: Discussionmentioning

confidence: 99%

Ablation of MMP9 Gene Ameliorates Paracellular Permeability and Fibrinogen–Amyloid Beta Complex Formation during Hyperhomocysteinemia

Muradashvili

Tyagi

Metreveli

et al. 2014

J Cereb Blood Flow Metab

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Increased blood level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) accompanies many cognitive disorders including Alzheimer's disease. We hypothesized that HHcy-enhanced cerebrovascular permeability occurs via activation of matrix metalloproteinase-9 (MMP9) and leads to an increased formation of fibrinogen-b-amyloid (Fg-Ab) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-b-synthase heterozygote (Cbs þ / À , a genetic model of HHcy), MMP9 gene knockout (Mmp9 À / À ), and Cbs and Mmp9 double knockout (Cbs þ / À /Mmp9 À / À ) mice using a dual-tracer probing method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg-Ab complex formation was assessed in mouse brain cryosections by immunohistochemistry. Short-term memory of mice was assessed with a novel object recognition test. The cerebrovascular permeability in Cbs þ / À mice was increased via mainly the paracellular transport pathway. VE-cadherin expression was the lowest and Fg-Ab complex formation was the highest along with the diminished short-term memory in Cbs þ / À mice. These effects of HHcy were ameliorated in Cbs þ / À /Mmp9 À / À mice. Thus, HHcy causes activation of MMP9 increasing cerebrovascular permeability by downregulation of VE-cadherin resulting in an enhanced formation of Fg-Ab complex that can be associated with loss of memory. These data may lead to the identification of new targets for therapeutic intervention that can modulate HHcy-induced cerebrovascular permeability and resultant pathologies.

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“…Homocysteine has been related to the risk of developing AD in some (159,160) but not all studies (161) and remains a topic of interest. The mechanism for association is not known, although homocysteine and folate deficiency have been shown to be neurotoxic in mouse models of AD (162,163) . Commonly, observational studies and randomised trials that examine nutrient effects on disease processes do not consider dose level when interpreting study results and trial design and, as noted earlier, this consideration is particularly important for folate because of folic acid fortification in some countries.…”

Section: B-vitamins Cognitive Decline and Alzheimer's Diseasementioning

confidence: 99%

Nutritional determinants of cognitive aging and dementia

2011

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The objective of this review is to provide an overview of nutritional factors involved in cognitive aging and dementia with a focus on nutrients that are also important in neurocognitive development. Several dietary components were targeted, including antioxidant nutrients, dietary fats and B-vitamins. A critical review of the literature on each nutrient group is presented, beginning with laboratory and animal studies of the underlying biological mechanisms, followed by prospective epidemiological studies and randomised clinical trials. The evidence to date is fairly strong for protective associations of vitamin E from food sources, the n-3 fatty acid, DHA, found in fish, a high ratio of polyunsaturated to saturated fats, and vitamin B 12 and folate. Attention to the level of nutrient intake is crucial for interpreting the literature and the inconsistencies across studies. Most of the epidemiological studies that observe associations have sufficient numbers of individuals who have both low and adequate nutrient status. Few of the randomised clinical trials are designed to target participants who have low baseline status before randomising to vitamin supplement treatments, and this may have resulted in negative findings. Post-hoc analyses by some of the trials reveal vitamin effects in individuals with low baseline intakes. The field of diet and dementia is a relatively young area of study. Much further work needs to be done to understand dietary determinants of cognitive aging and diseases. Further, these studies must be particularly focused on the levels of nutrient intake or status that confer optimum or suboptimal brain functioning. Nutrition: Cognitive decline: Dementia: Antioxidant nutrients: Dietary fatsAfter more than a decade of research on nutrition and the aging brain, a number of promising nutritional factors have emerged that are also important to neurocognitive development. This review describes the evidence for these nutritional factors that show the most promise in the prevention of neurodegenerative disease. Among these are antioxidant nutrients, B-vitamins, dietary fat composition and n-3 fatty acids. Each of these factors has a body of literature to support underlying biological mechanisms for association as well as evidence of association from prospective epidemiological studies. The clinical trial evidence for vitamin supplements has been disappointing, but very few of these trials were designed to test whether supplementation is effective in persons who have low nutrient status for that particular dietary component.In general, potential recommendations to maintain a healthy brain reflect those that have been demonstrated to maintain a healthy heart: physical activity combined with a diet that has a high ratio of unsaturated to saturated fats, vegetables, fruits and fish. In this review, we first describe common neurodegenerative diseases of aging and some basic fundamentals in nutrient absorption and physiological function. These sections are followed by a review of the evidence for each die...

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Homocysteine potentiates β‐amyloid neurotoxicity: role of oxidative stress

Cited by 260 publications

References 39 publications

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

Ablation of MMP9 Gene Ameliorates Paracellular Permeability and Fibrinogen–Amyloid Beta Complex Formation during Hyperhomocysteinemia

Nutritional determinants of cognitive aging and dementia

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