Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus

Zhang, Change; Tian, Qing; Wei, Wei; Peng, Jun-Hua; Liu, Gong‐Ping; Zhou, Xin‐Wen; Wang, Qun; Wang, Daowen; Wang, Jian‐Zhi

doi:10.1016/j.neurobiolaging.2007.04.015

Cited by 141 publications

(126 citation statements)

References 61 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Total catalytic PP2A c actually increased in TO cells despite the relative demethylation of its C-terminal leucine residue, which was reported to have key functional consequences (16). This relative demethylation could result either from a deficient transmethylation due to the decreased SAM/SAH ratio, or from the activation of a methylesterase by homocysteine accumulation (17). Our data suggested that the reduction in growth of the TO cells was mediated by an inhibition of the MAPK/ERK1/2 pathway through PP2A c up-regulation, as reported in vitro and by knock out experiments in Drosophila Schneider 2 cells (18,19).…”

Section: Discussionsupporting

confidence: 74%

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Battaglia-Hsu

Akchiche

Noel

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Vitamin B12 (cobalamin, Cbl) is indispensable for proper brain development and functioning, suggesting that it has neurotrophic effects beside its well-known importance in metabolism. The molecular basis of these effects remains hypothetical, one of the reasons being that no efficient cell model has been made available for investigating the consequences of B12 cellular deficiency in neuronal cells. Here, we designed an approach by stable transfection of NIE115 neuroblastoma cells to impose the anchorage of a chimeric B12-binding protein, transcobalamin-oleosin (TO) to the intracellular membrane. This model produced an intracellular sequestration of B12 evidenced by decreased methyl-Cbl and Sadenosylmethionine and increased homocysteine and methylmalonic acid concentrations. B12 deficiency affected the proliferation of NIE115 cells through an overall increase in catalytic protein phosphatase 2A (PP2A), despite its demethylation. It promoted cellular differentiation by improving initial outgrowth of neurites and, at the molecular level, by augmenting the levels of proNGF and p75 NTR . The up-regulation of PP2A and pro-nerve growth factor (NGF) triggered changes in ERK1/2 and Akt, two signaling pathways that influence the balance between proliferation and neurite outgrowth. Compared with control cells, a 2-fold increase of p75 NTR -regulated intramembraneous proteolysis (RIP) was observed in proliferating TO cells (P < 0.0001) that was associated with an increased expression of two tumor necrosis factor (TNF)-␣ converting enzyme (TACE) secretase enzymes, Adam 10 and Adam 17. In conclusion, our data show that B12 cellular deficiency produces a slower proliferation and a speedier differentiation of neuroblastoma cells through interacting signaling pathways that are related with increased expression of PP2A, proNGF, and TACE.homocysteine ͉ neurotrophin V itamin B12 (B12, also named cobalamin, Cbl) deficiency has long been associated with pernicious anaemia (1) and neurological disorders that range from minor behavior changes to severe neurodegenerative disorders (2). Molecular mechanisms are still lacking to explain how the deficiency can bring about all of the symptoms observed. Indeed, only two enzymes are B12-dependent in mammalian cells: the mitochondrial enzyme L-methylmalonyl-CoA mutase (EC 5.4.99.2) and the cytoplasmic homocysteine methyltransferase, also referred as methionine synthase (EC 2.1.1.13). Inferences are thus based on the two direct consequences of B12 deficiency: the accumulation of methylmalonic acid (MMA) and homocysteine (Hcy). Until now, the consequences of B12 deficiency in the brain have been difficult to evidence because of the experimental limitations of the classical cell models. Indeed, the minute amount of vitamin B12 needed by cells can be provided in vitro by B12 from the FCS, which can bind the ''autocrine'' B12 carrier protein, transcobalamin (TC) (3, 4).To delineate the role of B12 in neurological disorders, we designed a neuronal cell model made deficient in B12 through the stable ...

show abstract

Section: Discussionsupporting

confidence: 74%

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Battaglia-Hsu

Akchiche

Noel

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The deposition of neurofibrillary tangles is caused by the formation of phosphorylated τ, and raised tHcy concentrations lead to an increase in phosphorylated τ (37,38). Thus, lowering tHcy may decrease levels of phosphorylated τ and thereby reduce the degree of regional GM atrophy.…”

Section: Discussionmentioning

confidence: 99%

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

Douaud

Refsum

Jager

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

425

317

View full text Add to dashboard Cite

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 μmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.T he prevention of Alzheimer's disease (AD) is a major public health challenge, but several promising therapies targeting β-amyloid have failed in late-stage clinical trials (1). An alternative approach is to modify nongenetic risk factors and to treat people at risk of developing dementia before they develop the major symptoms (2, 3). Many cross-sectional and prospective studies have shown that raised levels of plasma total homocysteine (tHcy) are associated with cognitive impairment, AD, or vascular dementia (4-9), but randomized, controlled trials of tHcy-lowering treatment using B-vitamin supplementation have shown inconsistent results on cognitive function (10, 11). Factors such as dosage, vitamin combination, duration of treatment and the population treated possibly account for some of the discrepancies (10, 11). Another factor that may explain the discrepancies in these trials is baseline tHcy concentration: for instance, it has been found that subjects with modestly raised tHcy experience a beneficial effect of B-vitamin treatment on cognitive decline (12, 13).For trials with the aim of slowing progression of cognitive decline, the usual design includes neuropsychological assessments. Unfortunately, such testing is subject to short-term fluctuations, practice effects and intra-/interrater variability. In contrast, structural neuroimaging provides a robust way of as...

show abstract

“…We reported previously that the activity of PP-2A decreased and the activity of GSK-3 did not change in the hyperhomocysteinemia rats. 29 Here, we measured the expression and the activity-dependent modification of JNK, Cdk-5, and its modulators, p35 and p25. We found that the expression of JNK did not change but the phosphorylated JNK (p-JNK, the active form) decreased significantly after the injection of Hcy, and folate and vit-B12 restored partially Hcy (400 g/kg/day) was injected into the rats for 2 weeks with or without supplement of folate and Vit-B12 (FB, 250 g/kg/day).…”

Section: Hyperhomocysteinemia Decreases the Level Of P-jnk And P25mentioning

confidence: 99%

“…28 Recently, we have reported that hyperhomocysteinemia can increase prominently the plasma Hcy level and thus induce tau hyperphosphorylation. 29 In a hyperhomocysteinemic AD transgenic mouse model, an increased A␤ level in the brain was observed, 30 and Hcy could interrupt DNA repair in hippocampal neurons and make the neurons more vulnerable to the amyloid toxicity. [31][32][33] Until now, the effects of hyperhomocysteinemia on A␤ production in normal gene background and the underlying mechanisms leading to A␤ overproduction have not been reported, and it is also not known whether the induced hyperhomocysteinemia in adulthood affects the memory of the rats.…”

mentioning

confidence: 99%

Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

Zhang

Wei

Liu

et al. 2009

The American Journal of Pathology

Self Cite

132

122

View full text Add to dashboard Cite

Hyperhomocysteinemia and ␤-amyloid (A␤) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that A␤ levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of ␥-secretase, were elevated, whereas the expression levels of ␤-secretase and presenilin-2 were not altered. We also observed that levels of phosphorylated APP at threonine-668, a crucial site facilitating the amyloidogenic cleavage of APP, increased in rats with hyperhomocysteinemia, although the phosphorylation per se did not increase the binding capacity of pT668-APP to the secretases. The enhanced phosphorylation of APP in these rats was not relevant to either c-Jun N-terminal kinase or cyclin-dependent kinase-5. A prominent spatial memory deficit was detected in rats with hyperhomocysteinemia. Simultaneous supplementation of folate and vitamin-B12 attenuated the hyperhomocysteinemia-induced abnormal processing of APP and improved memory. Our data revealed that hyperhomocysteinemia could increase A␤ production through the enhanced expression of ␥-secretase and APP phosphorylation , causing memory deficits that could be rescued by folate and vitamin-B12 treatment in these rats. It is suggested that hyperhomocysteinemia may serve as an upstream factor for increased A␤ production as seen in patients with Alzheimer disease.

show abstract

Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus

Cited by 141 publications

References 61 publications

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

Contact Info

Product

Resources

About