B Vitamin Deficiency Promotes Tau Phosphorylation Through Regulation of GSK3β and PP2A

Nicolia, Vincenzina; Fuso, Andrea; Cavallaro, Rosaria A.; Luzio, Andrea Di; Scarpa, Sigfrido

doi:10.3233/jad-2010-1284

Cited by 64 publications

(44 citation statements)

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“…Unlike homocysteine, SAH levels in the plasma are not related to vitamin B6, vitamin B12, or folic acid concentrations [11,12]. Therefore, the SAH-vascular injury-AD axis may be considered one of several mechanisms linking homocysteine metabolism to the development of AD pathology [13][14][15]. Given the increasing evidence of the detrimental vascular effects of SAH, it would be of considerable interest to see a large-scale, prospective study of the relationship between plasma or cerebrospinal fluid levels of SAH and the development of AD.…”

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confidence: 99%

S-Adenosylhomocysteine: A Better Marker of the Development of Alzheimer's Disease than Homocysteine?

Chang

Chen

2010

JAD

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The article by Popp and colleagues [1] highlights the association between the alteration in homocysteine metabolism and Alzheimer's disease (AD) pathology (as reflected by the cerebrospinal fluid biomarkers amyloid-β 1−42 and P-tau181). Moreover, they raise the question as to whether S-adenosylhomocysteine (SAH) is a better marker of the development of AD than homocysteine. Although Popp and colleagues [1] found that phosphorylated tau was strongly associated with SAH rather than homocysteine, they did not study the mechanism underlying the SAH-AD association. The data from clinical and epidemiologic studies do not consistently show that plasma levels of homocysteine are associated with an increased risk of cognitive impairment and AD [2][3][4]. Similarly, clinical trials of vitamin B supplementation as a means of lowering homocysteine levels to prevent cognitive decline in AD patients have not been consistently successful [5,6] increasing evidence indicates that high plasma levels of homocysteine may not be a marker of vascular injury [6], the finding by Popp and colleagues that SAH, not homocysteine, is associated with tau accumulation in AD patients is not surprising.Vascular injury is an essential component underlying both AD and cognitive impairment in the elderly. The relationship between hyperhomocysteinemia and vascular disease is somewhat controversial. Increasing data suggest SAH is a better indicator of cardiovascular disease and atherosclerosis than is homocysteine [7,8]. In neurodegenerative diseases, elevated homocysteine levels can lead to higher brain levels of SAH and, in turn, increase phosphorylation of tau [9], supporting the crucial role of SAH in the development of AD. Despite the strong association of increased SAH and tau in AD patients, the molecular mechanisms of SAH-induced neuronal injury (which are most likely vascular) are not clear [7,8]. We have recently studied the mechanisms involved in vascular damage induced by homocysteine and SAH [10].In our study, exposure of human coronary artery endothelial cells to homocysteine alone, even at supra-

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confidence: 99%

S-Adenosylhomocysteine: A Better Marker of the Development of Alzheimer's Disease than Homocysteine?

Chang

Chen

2010

JAD

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“…So low folate status and elevated homocysteine besides the well-established roles on induction of DNA damage, increase the generation of reactive oxygen species and contribute to excitotoxicity, mitochondrial dysfunction and apoptosis. Also, low folate levels determine an imbalance between glycogen synthase kinase 3-beta (GSK-3b) and protein phosphatase 2A (PP2A) activity, leading to abnormal hyperphosphorylation of tau in AD 30 . Finally, methionine may be converted to S-adenosylmethionine (SAM), the principal methyl donor in most biosynthetic methylation reactions.…”

Section: Discussionmentioning

confidence: 99%

Redução dos níveis séricos de ácido fólico em pacientes com a doença de Alzheimer

Almeida¹,

Brentani²,

Forlenza³

et al. 2012

Rev. psiquiatr. clín.

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Background: Complex B vitamin deficiency has been associated to cognitive impairment and dementing disorders in the elderly. Objective: This work aims to assess whether patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) have lower levels of folic acid and cobalamin (vitamin B 12 ) compared to age and gender-matched controls. Methods: One hundred and forty six elderly subjects (40 AD, 56 MCI and 49 healthy older adults) were recruited for this study. Serum folic acid and vitamin B 12 levels were measured by electrochemoluminescence. Results: Compared to MCI and healthy controls a statistically significant reduction in serum concentrations of folic acid in AD patients was found (p = 0.02). This result remained statistically significant after controlling for socio-demographic and cognitive performance variables (p = 0.01). No significant differences were found in serum concentrations of vitamin B 12 in patients with AD, MCI and healthy controls. No significant changes in hematologic parameters were observed across these diagnostic groups. Discussion: The present study provides additional evidence that folic acid is reduced in patients with AD and reinforces the importance of nutritional changes, in particular the one-carbon metabolism, in the physiopathology of AD.

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“…Finally, it has also been demonstrated that the alteration of one-carbon metabolism and redox homeostasis by B vitamin deficiency and SAM supplementation was associated to tau metabolism by restoring PP2A activity and normal Tau phosphorylation [97]. Furthermore, in the same animal model SAM also prevents oxidative stress by modulating GSH metabolism and SOD activity [104].…”

Section: Involvement Of Sam In Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

“…It has been recently shown that alteration of one-carbon metabolism regulates expression of two key enzymes in the amyloid pathway: β-secretase (BACE1) and presenilin (PSEN1), such that low methylation potential is associated with increased Aβ production [47,[95][96]. Furthermore, activation of protein phosphatase 2A (PP2A) is SAM-dependent, and disturbed methylation status is associated with increased phosphorylation of tau, another phenomenon strictly implicated in the pathogenesis of AD [97][98]. Low methylation status is strongly associated with neurological and cognitive deficits.…”

Section: Involvement Of Sam In Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

Cavallaro¹,

Fuso²,

D’Erme³

et al. 2016

Int J Clin Nutr Diet

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S-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. SAM level in the organism decreases with aging and restoring the original levels through exogenous supplementation is an important tool for the improvement of many vital functions. Indeed, SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis and senile neurological disorders such as Alzheimer's and Parkinson's diseases. Recent evidences indicate that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator of different metabolic pathways involved in the antioxidant response in brain related disorders. Role of S-adenosylmethionine in the Modulation of Oxidative StressRelated Neurodegeneration Review ArticleOpen Access IntroductionThe interaction between environmental and genetic factors plays a fundamental role in inducing and modulating the aging processes towards brain disorders. Among environmental factors, diet and nutritional lifestyle have a key role in brain health through the alteration of the intake or the bioavailability of metabolites and cofactors. Specific nutritional factors have particular impact on one-carbon metabolism, which is a complex biochemical pathway regulated by the presence of folate, vitamin B12 and B6 (among other metabolites) and leading to the production of S-adenosyl-L-methionine (SAM), the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. This metabolism involves three interrelated biochemical pathways: folate cycle, transsulfuration pathway and methionine cycle. These three metabolic sequences were first combined and correlated in 1964 by Laster's group [1][2][3] giving the integrated point of view of transmethylation and transsulfuration pathways, linking sulfur amino acid metabolism to the provision of methyl groups for many biochemical processes. Normal functioning of this metabolic cycle is essential for growth and development and impairment of this metabolism; transmethylation efficiency is associated with many diseases like cardiovascular diseases [4][5], liver diseases [6-9], neural tube defects [10] and brain diseases [11][12][13][14][15][16]. One-carbon metabolism alterations, low methylation and oxidative stress are all linked to Late Onset Alzheimer's Disease (LOAD) [17][18][19][20][21][22][23][24] Moreover, wide confirmed reports underline the role of SAM dependent reactions in age related neurodegeneration also showi...

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B Vitamin Deficiency Promotes Tau Phosphorylation Through Regulation of GSK3β and PP2A

Cited by 64 publications

References 56 publications

S-Adenosylhomocysteine: A Better Marker of the Development of Alzheimer's Disease than Homocysteine?

S-Adenosylhomocysteine: A Better Marker of the Development of Alzheimer's Disease than Homocysteine?

Redução dos níveis séricos de ácido fólico em pacientes com a doença de Alzheimer

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

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