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REVIEW ARTICLE ISSN: 1573-4013 eISSN: 2212-3881

Homocysteine in Neurology: From Endothelium to Neurodegeneration BENTHAM SCIENCE

Rita Morettia,*, Matteo Dal Benb,c, Silvia Gazzinb and Claudio Tiribellib,c a

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy; bItalian Liver Foundation, Centro Studi Fegato, SS14, Km 163.5, Trieste, 34149, Italy; cDepartment of Medical, Surgical, and Health Sciences, University of Trieste, Trieste, Italy

Received: September 23, 2016 Revised: January 17, 2017 Accepted: February 02, 2017

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DOI: 10.2174/1573401313666170213155338

rS o ic r a le D is tri bu tio n

A R T I C L E H I S T O R Y

Abstract: Vitamin B12 and folate are supplied via two major pathways, the conversion of homocysteine to methionine and the conversion of methyl malonyl coenzyme A to succinyl coenzyme A. Therefore, the defect in both the vitamins results in an increase in both serum homocysteine and methylmalonic acid. Hence, homocysteine, vitamin B12, and folate are closely linked together in the so-called one-carbon cycle, making vitamin B12 the necessary co-enzyme for the methyl donation from 5-methyl-tetra-hydrofolate in tetra-hydro-folate, necessary for methionine synthetase. Folate is a cofactor in one-carbon metabolism, and it promotes the remethylation of homocysteine, which can cause DNA strand breakage, oxidative stress and apoptosis. Vitamin B12 and folate are involved in nucleic acid synthesis and in the methylation reactions, and their deficit causes the inhibition of S-adenosylmethionine mediated methylation reactions, and through the related toxic effects of homocysteine, a possible direct alteration of the vascular endothelium and inhibition of N-methyl-D-Aspartate receptors take place. We discussed the possible and still controversial role of homocysteine accumulation in cerebral pathologies, starting from vascular events to neurodegeneration and to endothelium damage mechanism.

1. INTRODUCTION

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Keywords: Homocysteine, folate, vitamin B12-cobalamin, dementias, psychiatric symptoms, vascular endothelium, folate-vitamin B12 supplementation, therapy.

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2. BIOCHEMICAL LINKS BETWEEN COBALAMIN (VITAMIN B12), FOLATE AND HOMOCYSTEINE

The pathway of one-carbon metabolism activates onecarbon units, normally from serine, tighten to tetrahydrofolate. The produced 5,10-methylentetrahydrofolate is employed for the production of thymidylate and purines (fundamental for nucleic acid synthesis) and of methionine, fundamental for methylation-process [7]. The methionine synthesis is anticipated by the reduction of 5,10-methylentetrahydrofolate to 5-methyltetrahydrofolate (5-methylTHF) catalysed by the flavin-containing methylenetetrahydrofolate reductase [7]. 5-methyltetrahydrofolate is the substrate to methylate homocysteine, employing vitamin B12 as a catalyzer [7]. Methionine adenosyltransferase (MAT) catalyzes S-adenosylmethionine (AdoMet), in a reaction involving methionine and ATP [8, 9], and every reaction made by methyltransferases produces S-adenosylhomocysteine (AdoHcy) which is a potent inhibitor of most of them [9-11].

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When one discuss homocysteine, he should declare that he will also speak about folate and vitamin B12 [1-5]. Homocysteine is not involved in protein synthesis, rather as an intermediate in methionine metabolism [5] and it is either degraded via the remethylation pathway or converted, via the transsulfuration pathway into cysteine [5] (Fig. 1).

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Current Nutrition & Food Science

Being that folate and vitamin B12 are necessary for the methylation process, and that these reactions are fundamental to the biochemical basis of brain metabolism, the deficiency of vitamin B12 and folate can have possible consequences in neurological diseases [4, 5]. Vitamin B12 transfers the methyl group to homocysteine and is determinant in the synthesis of methionine, which is needed for the syn-thesis of S-adenosylmethionine (SAM), the sole donor in numerous methylation reactions involving proteins, phospholipids and biogenic amines [6]. We discuss different results from many experimental studies on the topic.

*Address correspondence to this author at the Department of Medical, Surgical, and Health Sciences, University of Trieste, Trieste, Italy; Tel: +39-040-399-4572, E-mail: [email protected]

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In general, AdoHcy hydrolase (SAHH) acts on AdoHcy, producing adenosine and homocysteine [10, 11], and they need to be metabolized or transported out of the cell, to prevent their accumulation [11, 12]. This hydrolysis is a reversible reaction that favors S-Adenosyl-L-homocysteine (SAH) synthesis. This event occurs regularly in the case of

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164 Current Nutrition & Food Science, 2017, Vol. 13, No. 3

Moretti et al.

Homocysteine accumulation Psychiatric symptoms (schizophrenia, depression, mental retardation) Dementias Arterial and venous occlusive disease Damage to the vascular endothelium Inhibition/enhancement of NMDA (depending on glycine availability) DNA strand breakage Oxidative stress Apoptosis

Vit B12 deficiency Dementias (debated) Peripheral Neuropathy

Folate deficiency Developmental delay Cognitive deterioration Motor & gait abnormalities Behavioral & psychiatric symptoms Seizures Demyelination defects Vascular dementia & stroke Cerebral atrophy

CYSTEINE CBS

SAM

Nucleic Acid Synthesis SAM

HOMOCYSTEINE MTHF

SAH

Met-THF Proteins from diet

MTR

Inactive folates from diet


Methylation Reactions (Proteins Phospholipids Biogenic Amines)

MTHFR

Glycine

M-B12

SAM

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Methionine

A-B12

MMA-CoA

S-CoA

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AA & Odd chain FA

Serine

THF

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Fig. (1). The one carbon cycle with special emphasis to the brain. Blue circle: Methionine cycle. MTR: Methionine Synthase; M-B12: Methyl Cobalamine. SAM: S-Adenosyl-Methionine; SAH: S-AdenosylL-Homocysteine. Purple Circle: Trans Sulfuration Pathway. CBS: Cystathionine Synthase. Pink circle: Folate Cycle. MTHF: MethlyTetraHydroFolate; MTHFR: Methylene TetraHydroFolate Reducatse; Met-THF: Methylene-TetraHydroFolate. THF: Tetrahydrofolate. Yellow circle: AA: Amino Acids; FA: Fatty Acids; MMA-CoA: Methtyl-malonyl Coenzyme A. A-B12: Adenosyl Cobalamine. S-CoA: Succinyl-CoA. Green circles: Key players involved in homocysteine recycling.

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folate or vitamin B12 deficiency, leading to SAH intracellular accumulation [7, 12, 13]. If homocysteine is allowed to accumulate in normal conditions, it will be rapidly metabolized to SAH, which competes with SAM, for the active site on the methyltransferase system [6, 13-16]. The oxidation of homocysteine to homocysteic acid is one of the potential explanations with many dangerous effects of homocysteine, due to the fact that it is a mixed excitatory agonist of NMDA receptors [17]. Homocysteine is also methylated by betaine [6, 12,18], not operative in the brain [19-21]. Homocysteine remethylation is catalyzed by the methionine synthase (MTR) enzyme [19] and this is the keypoint of anchorage between folate, vitamin B12, and homocysteine. MTR requires vitamin B12 (Cbl) [9, 19, 22, 23]. During the transsulfuration pathway, homocysteine is irreversibly degraded to cysteine [6-11]. Cysteine is a precursor of glutathione, the most fundamental endogenous antioxidant [6, 11, 24]. In most tissues, homocysteine is either remethylated or exported out of the cell [6]. The liver is the main organ of

degradation of excess methionine and in maintaining homocysteine at adequate levels [11]. In the liver, there is a direct and univocal correspondence, between the increase of methionine and a concomitant increment of AdoMet [6, 7, 11], and due to an intrinsic auto regulatory system, AdoMet inhibits methylenetetrahydrofolate reductase (MTHFR) and activates CBS activity [25-28].

Excess methionine causes an important homocysteine degradation, via the transsulfuration pathway. Lack of methionine conserves homocysteine, via remethylation back to methionine [11, 21, 24]. Therefore, 5-methylTHF functions as a methyl donor for homocysteine remethylation [26-29]. The resulting tetrahydrofolate (THF) can directly be converted into 5,10methyleneTHF by the action of serine hydroxymethyltransferase (SHMT) [27-29]. The conversion of THF into 5,10methyleneTHF is catalyzed by methylenetetrahydrofolate dehydrogenase (MTHFD1) [26-29]; MTHFR enzyme, therefore, regulates the passage from 5-methyl THF to homocysteine remethylation [29].

Homocysteine in Neurology

Current Nutrition & Food Science, 2017, Vol. 13, No. 3

3. FOLIC ACID Dietary folic acid predominantly exists as polyglutamate, which have to be hydrolyzed to monoglutamates in order to be available [6]. To hydrolyze folic acid, in the gut, the folylpoly-gamma-glutamate carboxypeptidase (FGCP) is fundamental, anchored to the intestinal apical brush border and encoded by the glutamate carboxypeptidase II (GCPII) gene [6, 30, 31, 33]. Mono-glutamylated folates are then captured in the duodenum and in the upper part of the jejunum, by the high-affinity proton-coupled folate receptor (PCFT1) [32-34].

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Additionally, in hematological conditions, where there is a defect in homocysteine methyltransferase, or when there is a combined deficiency of B12 and hcy-methyltransferase, a specific, though rare, combined effect occurs, defined as "methyl-trap" of tetrahydrofolate; THF is converted to a reservoir of methyl-THF, and therefore folic acid is trapped and cannot be employed [42]. 4. VITAMIN B12

Only in the most severe cases of gastric atrophy does intrinsic factor secretion become a rate-limiting factor for vitamin B12 absorption [7]. Most frequently, atrophic gastritis enhances the impaired release of vitamin B12 from food proteins and peptides due to impaired acid secretion [6, 7]. Vitamin B12 deficiency might be common in the frailest population including children and elderly [44]. There are different causes which can produce cobalamin deficiency: an inadequate intake (vegans, and also vegetarians but to a lesser degree, see the next chapter), malabsorption (a. inadequate production of intrinsic factor; b. disorders of the terminal ileum, Crohn’s disease and small bowel syndrome; c. competition for cobalamin, in particular in the so-called blind loop syndrome and celiac disease) [2, 3-6, 41], drugs (such as ranitidine, metformin, anticonvulsivants, chemotherapy agents, alcohol etc.), genetic deficiency of transcobalamin II [2, 41-44]. 5. FOLIC ACID AND VITAMIN B12: THEIR INTRINSIC CLINICAL RELATIONSHIP There is an intimate, biochemically known but not completely clinically understood, relationship between folic acid and vitamin B12, as highlighted in some clinical observations. Treating a B12 deficient patient with folate or conversely a folate deficient patient with B12 may exacerbate the neurologic consequences or either deficiency [6, 45-47]. The finding of such few “pure” cases reported from the literature of dementia due to vitamin B12 defect (even considering the wide-spectrum of possible causes of its defects) may be suggestive of different possible interactions of this defect to another causative role, such as folate exposure. We have reported four cases [46], where the onset of cognitive impairment due to a lack of vitamin B12 has been determined by a concomitant and erroneous assumption of folate; even the other case [47] was “spurious” in the sense that the B12 defect was enriched with a concomitant intake of folate, and not supplemented directly by vitamin B12 [6, 46, 47].


There are many physiological conditions which require more folate in human life than necessary, such as the growing process, recovery from systematic illness, and pregnancy [35-39]. Pathological deficiency of folate may be determined by inadequate dietary intake, infectious status [6-38], and alcoholism [6-40]. Diffuse inflammatory or degenerative diseases of the small intestine, such as Crohn's disease and coeliac disease, may reduce the activity of pteroyl polyglutamase (PPGH), a specific hydrolase required for folate absorption, and thereby lead to folate deficiency [41]. Some other situations that increase the need for folate include the following: systemic or occult hemorrhage, kidney dialysis and chronic liver disease [40-43]. Medications might interfere with folate absorption, such as many anti-epileptic drugs (phenytoin, primidone, carbamazepine or valproate), or metformin; methotrexate; sulfasalazine; oral contraceptives; triamterene; many chemotherapeutic agents [6, 42-44].

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The central nervous system requires a constant supply of glucose, for the maintenance of ATP Na/K pumps, but also needs all the essential nutrients [29]. Some of them are B vitamins, which participate in one-carbon metabolism; their importance is so fundamental that congenital deficiency of them is associated with severe impairment of brain function [29]. The most frequent clinical conditions for B12 deficiencies is the aging process [2-29].

There are different causes which can produce B12 deficiency (inadequate intake, malabsorption, drugs interaction, genetic deficiency of transcobalamin II) [6-7]; however, the effective number of vitamin B12 defect-dementia is extremely small [1-6]. There are different cases reported in the literature of cognitive disruption (the formerly called “treatable dementia”) generically attributed only to the lack of B12 [45-47]. It has been hypothesized that the increase of vitamin B12 defect in aging patients might be related to the age-related changes in gastric histology, with atrophic gastritis with hypochlorhydria or achlorhydria, along with consequently decreased secretion of intrinsic factor [6, 7].

It has also been suggested that low levels of vitamin B12 reduce methylation reactions in brain tissue [6, 7]. Moreover, the lack of SAM, largely dependent on folate and vitamin B12, through the methylation reaction [6-18] might contribute to cognitive impairment derived from vitamin B12 and folate deficiency. Not fully understood is the rule that treating a B12 deficient patient with folate may exacerbate the neurological consequences of either deficiency, and as the good clinical practice recommends, cyanocobalamin deficiencies should be excluded before folate supplementation is commenced, or if necessary, it should be appropriate to supplement folate and vitamin B12 together [7, 45-56].

Very recently [44] the National Institutes of Health has confirmed, in general practice, that the supplementation of large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency. This problem can be determined by masking effects of laboratory evidence of megaloblastic anemia, originally caused by vitamin B12 deficiency [44]. Due to the fact that consumers may be ingesting more vitamins (folic acid and vitamin B12 can be obtained without a clinical prescription) than they realize, the NIH recommends


that folic acid intake from fortified food and supplements should not exceed 1,000 g daily in healthy adults [44]. 6. UPDATES OF NUTRITIONAL ASPECTS OF B12 AND FOLATE Since vascular factors and neurodegenerative problems have at the moment not therapeutic options, and nutrients may be modifiable risk factors, B complex, folate, Hcy and many others have received attention [57]. Recent data, [58, 59] showed a high prevalence of low dietary intakes for vitamin B (29-41%) in old patients and estimated 9-12% of older people in the UK who suffer from folate deficiency, due to their dietary intake. Data from other communities [60] reported that ischemic stroke patients had unfavorable dietary behaviors, with lower intake of fruit, vegetables, anti-oxidant and the intake of vegetables, fruits, vitamin C and folate were significantly associated with the risk of ischemic stroke, after adjusting for confounders.

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works have failed to confirm the optimistic results [68, 74, 75] and one of the prominent author on the topic declared that subnormal serum vitamin B12 levels are not an important cause of reversible dementia [75]. When taken into account the works which considered the role of the combined low serum levels of vitamin B12 and folic acid [4, 76], it can be evicted that in old people who are not demented, neither low level of vitamin B12 nor folate alone significantly affected the risk of developing AD [4, 76]. On the contrary, it can be observed that, compared with subjects with normal levels of vitamin B12 and folate, the very old patients with the lack of these vitamins showed high risk of developing AD [4]. Other reports [77] did not evidence cognitive and executive alterations. no significant modif Hassing et al. [78] showed that AD patients, correctly supplied with vitamin B12 and folic acid did not improve, but observed that they performed worse in neuropsychological tests when maintained with low folic acid levels [78]. One of the most significant and well-conducted studies on this topic, the so-called SENECA [79], showed no correlation between mental health and low levels of vitamin B12/folate status. The most interesting aspect in this riddle, is homocysteine; there are some studies, like the one by Nilsson et al. [80], which evidenced that patients affected by AD, who had elevated homocysteine plasmatic levels, and have been supplied by vitamin B12, perform better in neuropsychological tests [80]; on the contrary, if dementia’s scores are worse, no significant effect emerged from vitamin B12 supplementation [80]. After this study, Bryan et al. [81] obtained a significant improvement in memory recall, speediness of thought, of executive functions, and linguistic appropriateness, and any effect on mood, when more than 200 healthy middle-aged or older women have been supplied with folate, B12 and B6 vitamins [81].


The other emerging problem is the diet habits. Several authors [61], claimed that there are potential risks for vegetarians and vegans who should be advised to carefully plan their diets to monitor their vitamin B and folate levels on regular basis. In general, in the USA, the good clinical practice stated by the Institute of Medicine and recommended daily by the Harvard TH Chan School of Public Health [62, 63] recommended a general intake of 400 micrograms per day of folate, suggesting that people, who regularly drink alcohol, should intake at least 600 micrograms per day. Food sources of folate are fruits and vegetables, whole grains, beans, cereals, and fortified grains product. The recommended intake of vitamin B12 is 2.4 micrograms per day. It is found in fish, poultry, meat, eggs, dairy, fortified cereals, enriched soy or rice milk.

Moretti et al.

7. FOLIC ACID AND VITAMIN B12 DEFECTS: WHAT DO THEY DO IN REAL CLINICAL PRACTICE?

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Even if it has been reported in different papers [6, 50, 52] that vitamin B12 is a determinant factor causing one of the so-called treatable dementia, and Larner et al. [53, 54] reported an overview of literature suggesting that there are cases of dementia determined by vitamin B12 defect, the number of vitamin B12 defect-dementia is extremely small [6, 46, 47, 64-66]. Many studies evidenced lower serum vitamin B12 levels in subjects with Alzheimer Disease (AD) or other dementias [6, 67, 68]. One of the most profound studies [69] on the topic examined the relationship between vitamin B12 serum levels and cognitive and neuropsychiatric symptoms in dementia, and it is not clear if the defect should be related to the age of the population examined from the neurodegenerative aspects [6, 69]. However, there are many different studies which have documented the effectiveness of vitamin B12 supplementation, in improving cognition in demented patients [6, 69-72]. Another well-conducted study demonstrated that vitamin B12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia [6, 73]. Many other

Reynolds et al. [82] focused on the importance of folic acid deprivation as determinant factors for depression and worsening of demented patients, Recent studies [83-84] determined that errors in the folate transport system and the consequent lack of folic acid might cause in a development delay, cognitive alterations, motor clumsiness, behavioral alterations and signs of demyelination More recently [85], a large international double-blind placebo-controlled randomized trial, focused on many thousand women, who have previously experienced Neural Tube Defect (NTD) pregnancy; these women have been supplied by large doses of folic acid, and a reduction of NTD of 72% in the following pregnancy was demonstrated [85, 86]. In 1998, the obligatory folic acid fortification of cereal grain products had a direct consequence of a NTD decline rate of 20%. Data have been recently reproduced in larger studies [87]. Several mechanisms have been suggested to explain the possible link between folic acid lack and NTD [11]. As above reported, folic acid is related to DNA methylation, a fundamental regulating system in precocious embryogenesis [88, 89], and this might be related to the regulation of gene expression [89]. Folic acid relays on the correct functioning of the MTHFR enzyme, which acts as a donor of methyl groups, necessary for purines and pyrimidine synthesis [11]. Therefore, genetic micro-alterations of MTHFR (for example 677TT genotype) decrease the methylation capabilities [90], with a consequent



reduction of global DNA methylation [91, 92], related to NTDs [24]. NTD has been demonstrated in vitro, by the inactivation of DNA methyltransferase (DNMT3B) [93-95]. A reduced AdoMet/AdoHcy ratio, which causes an increase of Ado Hcy, and therefore inhibits DNA methylation has been found also in a single case of reported co-existence of trisomy 21 and spina bifida [96]. These studies lead to the conclusion that folic acid supplementation during pregnancy might prevent NTDs by donating methyl groups, thereby improving methylation and therefore it is strongly recommended [86-87]. Moreover, a lack of folic acid has been associated with an increase of homocysteine, in experimental mice, treated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), supporting the possible link between folic acid poorness and Parkinson’s Disease [97].

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The Canadian Study of Health and Ageing [102], a 5 years population-based survey, studied the potential risk of any cerebrovascular event, including vascular dementia, vascular cognitive impairment or fatal stroke, during a strickt follow-up of serum folate levels [102]. After adjusting for normal vascular risk factors (such as smoking, nutrition, diabetes, etc.), it emerged that the risk for a vascular event, associated with the lowest folate quartile was OR 2.42 (95% CI; 1.04-5.61) [102]. The same study demonstrated that a low folate level represents a higher risk for the development of vascular events, even in female patients (OR 4.02, 95% CI; 1.37-11.81) [102].

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development, as indicated by the observation that Hcy accumulation delays the closure of the neural tube, due to an inhibition of the transmethylation pathway [94]. A link between Hcy and neurological alterations has been described in patients with severe CBS deficiency [11-29], and in genetic metabolic alterations, which induced severe hyperhomocysteinemia (HHCY) (total homocysteine >50 uM) or homocystinuria, determined by genetic alterations of remethylation or transsulfuration pathways [11-29]. When there is an MTR deficiency or dysfunction, 5-methylTHF cannot cycle resulting in the accumulation of 5-methylTHF; folate does not circulate, limiting the synthesis of purines and thymidine [6-29]. These problems have been associated with congenital/genetic hyperhomocysteinemia condition, and they occur if the defect is located in the remethylation or in the transsulfuration cascade [29]. Numerous methylation reactions are strongly needed in the brain, for the synthesis and for the degradation of many neurotransmitters, and for the assemblage of many membrane phospholipids [29]. On the other hand, the transsulfuration pathway is a key point for Hcy catabolism; it accounts for glutathione synthesis in the liver but no clear data are available for the brain [29]. Many papers focus on this point, suggesting that some enzyme reactions, such as cystathionine beta synthase and cystathionase, act in the brain [29, 107-108], and could promote the transsulfuration of Hcy into cysteine, producing the precursor of glutathione [29-109]. Only a paper documented in an in vitro model production of glutathione by astroglia by cysteine and cystathionine [29-110].


It is known that a lack of folic acid is related to a higher percentage of depression, but the reason is not clear [98]. Since the folic acid is the substrate for SAM, and the role of methionine in monoamine metabolism is crucial, a reduction of the monamine-neurotransmitters synthesis, i.e. serotonine and gamma-amino butyric acid [99], may be related to depression. Folic acid level and homcysteine are indirectly related to years of age, they have been related to aging process [100, 101], and, therefore, to cerebrovascular pathologies, whose main unmodifiable risk factor remains aging process [100, 101].

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In a relatively small sample of 30 elderly Catholic sisters, affected by AD, a low folic acid level directly correlates with the severity of atrophy of the neocortex and with the amyloid deposition in the neocortex [78-103]. In the Kingsholmen aging and dementia project, in 250 old (75 to 96 years) and in 71 very old (90 to 101 years), otherwise healthy subjects, the altered memory recall has been related to folic acid low levels [104]. These findings have been reproduced with a significant correlation between lower cognitive function and raised homocysteine level and low folic acid levels [105]. 8. HOMOCYSTEINE: HOW DOES IT RELATE WITH FOLIC ACID AND VITAMIN B12 AND WHAT DOES IT CAUSES? Hcy is a sulfur-containing aminoacid, tightly related to methionine metabolism [29]. It seems involved in neural

Therefore, Hcy transsulfuration is not the fundamental reaction for the induction of the synthesis of in the brain [29, 111, 112]. It seems more probable that cysteine can be transported by a Na- dependent glutamate transporter in astrocytes. Cysteine is the rate-limiting substrate for the synthesis of glutathione [29, 113], and somehow, different cysteine precursors (cystathionine, homocysteine, and methionine) may have a major role in the production of glutathione in the brain [29, 113]. Animal models identify a specific saturable receptor for Hcy in the brain, which can implement a diffusion process [29, 114-116]; in humans, the diffusion process is the only known system of Hcy transport [29]. Human neuronal cells produce Hcy [117], but probably with different regional quantities, not investigated at the moment [29, 117]. As above mentioned, an increase of Hcy occurs in the brain and CSF within the aging process and in several neurological diseases, either in CSF either in plasma [29, 118122]. Severe HHCY (>100 lM) in children with CBS defect correlates with a 10-fold increase in concentrations of Hcy in CSF [123]; it is hypothesized also for human being, even if the finding is proved only in animal models, that Hcy might compromise the integrity of the blood-brain barrier [124]. Hcy is toxic for neurons [29, 125, 126]. Neurological damages have been reported in mice deficient in CBS enzyme (Cbs -/+ or Cbs -/-), where Hcy increased by approximately 2-50-fold in comparison to wild-type mice [125-131].


The mechanisms of damage, mediated by homocysteine, are various, and not always linked to plasma HHcy’ levels as high, but also a lower level of HHcy can act as a promoter of neurodegeneration, or potential inflammatory inducer. 9. HCY AND NEURODEGENERATION The mechanism of damage evoked for neurodegeneration is the link between Hcy and endogenous glutamate receptor, where Hcy acts as an agonist [29, 132, 133], and links NMDA receptors [134, 135].

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Another study suggested that Hcy can activate the group I metabotrophic glutamate receptors [29, 138]. This interaction can be demonstrated by blocking NMDA, non NMDA and metabotrophic glutamate receptor, via specific antagonists: a reduction of calcium influx can be observed, when binding these receptors [29, 136].

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A strong number of new works concentrate themselves on the active role of Hcy; it has been demonstrated that there is a direct relation between Hcy increase and Abeta 1-40 deposition, in aged brain and in brain of patients [140]. A specific endoplasmic protein, Hcy related (HERP) has been detected, and it potentiates the c-secretase activity, and consequently Ab1-40 accumulation in the brain [29, 141]. It has been described that Hcy increases the vulnerability of neurons to Abeta deposition damage [29, 142, 143] and that Hcy might potentiate the intracellular and extracellular accumulation of Abeta 42 [29, 144].

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ing a failure in post-translational modifications or in the stability of the enzyme [29, 152]. Low concentration of SAM (or an increase in SAH) determines a lower activity of PPA2 and, even indirectly, an elevation of P-tau [29, 153, 154]. The induced depletion of folic acid in neuroblastoma cultured cells induced directly (or as a consequence of the induced hyper-Hcy and ROS- this point is not clarified) an increase of P-tau by 66% [29, 117]. Hcy increases the toxicity of Abeta on the vascular smooth muscle cells of brain small arteries [155]. Therefore, due to their role in autoregulation, small arteries can be a potential site of damage of hyper Hcy, causing alteration of the cerebral blood flow regulatory system, a rupture of blood brain barrier, and therefore hyper Hcy might potentiate its direct neurotoxic effects [29, 142, 156]. 10. HCY, ROS, INFLAMMATION The activities of methionine synthase, CBS, that mediate the clearance of Hcy, is linked to the redox potential of the cells [29, 142, 157, 158], with an observed efficacy in oxidative stress process; in this situation, more Hcy is converted into cysteine and glutathione. A disruption of the CBS causes an altered redox homeostasis, and by an induced limitation of the cysteine and glutathione levels, it causes an alteration of oxidative repairing process [29, 157-162]. The endothelial damage is mediated by one of the precursors, hydrogen sulfide (H2S), which is formed during the transsulfuration process [29, 163, 164]. H2S serves as a vasodilator, it might contribute to the control of the vessel diameter and it regulates the intracellular signaling process; it might induce a defense against redox stress on the endothelium, (see above) and it probably acts by reducing the cascade of inflammation on endothelium [163, 164]. The disruption of the redox system in vascular and neuronal cells [29, 161, 162] (where it has been linked to an increment of ROS and deactivation of nitric oxide, with the well-known inflammation cascade) induces and accelerates the lipid peroxidation sequel of events [29, 165, 166]. In fact, different studies demonstrate that the employment of antioxidants, such as N-acetyl cysteine, vitamin E or C might reduce the potential pro-inflammatory response of Hcy in animal models [117, 167-169]. In vivo studies point on the controversial role in the damage of the endothelium. Different reports documented the Th1-activity induced the Hcy inflammation response [170], and it appears that HHcy can be detected in chronic inflammatory conditions, even if vitamin B12 and folate are in range. In a double-blind interventional study [171], the role of Hcy in atherogenesis in coronary diseases was shown; they found an association between neopterin’s and Il-6’ levels and HHcy at baseline. In this study the Authors found that the implementation with vitamin B complex does not affect inflammatory markers, such as neopterin, Il-6, CRP, etc.; on the contrary, the implementation of folate caused a disappearance of the relationship between HHcy and Neopterin, found at baseline, suggesting a possible modulating role of folic acid in the inflammatory cascade. Thus, they suggest that “an optimal folate status override the influence of immunostimulation on Th1 by Hcy” [171].


Through Hcy-NMDA binding, Hcy indirectly enhances calcium influx [132, 135, 136]. Glycine is the variable which conditions the Hcy effects [29]; when glycine is in normal concentration (10 umol/L), Hcy acts as a partial antagonist of the glycine site of the NMDA receptor, and it inhibits the receptor-mediated activity, acting as a neuroprotective factor [29, 132]. If glycine levels are normal, only HHcy is toxic (i.e., Hcy = 100umol/L) [29, 132]. When glycine levels increase in the nervous system (more than 10 umol/L), such as reported after brain ischemia, head trauma, or migraine cluster [29, 137], a relatively low concentration of Hcy (i.e., Hcy = 10 umol/L) can act as an agonist on NMDA [29, 132, 138, 139].

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Increasing attention has been given to the gene expression of Presenilin 1 (PS1), which is tightly related to methylation process in brain [29, 145, 146]; it promotes the APP production [29, 146]. DNA hypomethylation up-regulates PS1 gene, and increase APP [29, 146]. Moreover, tau protein, is equally related to methylation process; the protein phosphatase 1 (PPM1), whose methylation is SAM dependent, regulates the activity of the protein phosphatase 2A, which acts as a dephosphorylating system for tau protein, fundamental for its correct function [147, 148]; hyperphosphorylation of tau inhibits its normal function; it contrasts the assembly of microtubules and promotes the precipitation of neurofibrillary tangles: hence the reduced methylation capacity can increase P-tau [29, 147, 148]. The protein phosphatase 2A (PP2A) can dephosphorylate P-tau in paired helical filaments, making tau accessible to proteolysis, to avoid the accumulation of tangles [29, 149151]. The expression of the PP2A protein is low in AD patients [152] although mRNA PP2A is increased, suggest-



Ploder et al. [172] investigated the modification of Hcy plasma levels, in patients with multiple traumatic lesions, a consequent sepsis, and a systemic inflammatory response. The results showeda constant HHcy in sepsis patient with poor outcome (non-survivors), without evidence of any other factorial causes (such as folate or B12 poorness). The authors [172] hypothesized that the pro-inflammatory condition of these patients leads to a strong activation of macrophagesystem cascade by Hcy, with a consequent release of ample amounts of ROS, potentiating the oxidative stress. More recent results [173] demonstrate in vitro a definite activation of B lymphocyte induced by Hcy; this process seems to determine an increase of pyruvate kinase muscle isozyme 2 (PKM-2) in B cells. Its inhibition, employing shikonin, causes the restore of the metabolic changes induced by Hcy. PKM-2 seems to suggest the so-called metabolic accelerated initiation of atherosclerosis cascade mediated by HHcy, in vivo and in vitro [173].

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ROS released, of up-regulation of the Nuclear Factor Kappa B, considered as one of “the master regulator of the expression of inflammatory genes” [180, 181]. The lack of folic acid, associated with an increase of Hcy, might potentiate the oxidative induction of the transsulfuration reaction process [142-144]. This fact has been demonstrated also in animal experiments: if we consider apolipoprotein E-deficient mice or cultured neuronal cells deprived of folate, we can observe that the amelioration of the conditions with antioxidant agents (like SAM, or vitamin E) determines a reduction of the oxidative cascade [143, 182]. It should be mentioned the direct correlation between Hcy and SAH, in the reaction mediated by SAH-hydrolase [29]; therefore, a higher level of SA reduces the SAM concentrationand even the higher SAH level (or the lower SAM level) induces an oxidative reaction, and might explain Hcy neurotoxicity [13, 29, 129, 182]. Increasing SAM levels, or employing enriched SAM pabulum for cells neuronal tissues, might reduce apoptosis by 50% [29, 183-185]. 11. HCY AND VASCULAR DAMAGE


Li et al. [174] showed that in animal models, an induced hyper-Hcy produces a higher plasma level of Tumor Necrosis Factor alpha (TNF-) and of Interleukin 1 beta (IL-1) andan evident decrease of plasma levels of H2S and of cystathionine gamma-lyase expression in the peritoneal macrophages [174]. It has been demonstrated that hyper-Hcy inhibits cystathionine -lyase expression and H2S production in macrophages; HHcy is related to an increase of the DNA expression of methyltransferase and of hypermethylation process in promoter regions [174], therefore inducing a promoter trigger of inflammation. These results have been confirmed by other reports [175-177] which showed that higher levels of Hcy promote, in many different experimental conditions, the activity of specific genes, implicated in the methylation process, and therefore [175-177] HHcy induces inflammation of the endothelium matrix and triggers atherosclerosis process. A single study [178] confirmed the previously reported study, and showed that Hcy alters the transcriptional repression of fibroblast growth factor 2 [178]. Li et al. [174] definitively demonstrated that cultured macrophages cells exposed to Hcy showed a memory response, probably induced by epigenetic mutations, that influences the expression of promoter genes inflammatory response and endothelium atherogenesis [174].

169

There is a possible link between the excitotoxic effect of Hcy and the pro-inflammatory role of Hcy: the NMDA receptors are found not only in neurons (see above in the text), but also on neutrophils and macrophages. The activation of these receptors in the immune-competent cells induces an increase in the cytoplasmatic calcium influx, and an activation of a pro-inflammatory cascade, with an accumulation of ROS species [179]. To confirm these aspects, a new series of studies have been conducted in many systemic inflammatory diseases, where multi-factorial aspects (genetic, epigenetic, auto-immunitary) are involved, and where the risk of concomitant cerebral and cardio-vascular pathologies is very high. A good example is the Reumatoid Arthritis [180] where HHcy is two times more frequent than in the general population [180]. In Rheumatoid Arthritis, HHcy creates a chronic condition of oxidative stress, of prothrombotic induction, and, indirectly, by the excess of

Increased levels of Hcy, both in CSF and in plasmatic concentration, as far as aging increment [29, 183-185]; that seems quite thought-provoking, considering the tight relationship between aging and the incidence of neurodegenerative disorders [29, 183-185]. Moreover, the most antique link between Hcy and brain altered function is the white matter damage (vascular micro-alterations) evidenced by neuroimaging, in many population studies [29, 186]. Then, another, not independent association, between brain aging, Hcy and cortical and subcortical atrophy [29, 187] has been demonstrated. But even more compelling is the association between Hcy, vascular effects and its neurotoxic intrinsic potential; this triad of events occurs in vascular dementia, where amyloid cerebropathy is linked to small vessel disease and to Ach deregulation [129, 184-190]. Different studies have focused on the pure vascular damage related to hyper Hcy [29, 191, 192]. But the very first description of Hcy damages on endothelium derived from McCully [193]. He described for the first time two inborn errors of Hcy metabolism, with severe vascular damage and fatal circulation problems [194]. A recent study found that HHCy is related to high levels of fibrinogen and Abeta deposits in the blood vessels of AD patients [194]. Chung et al. [194] demonstrate that Hcy has the possibility to speed and to reinforce the interactions between fibrinogen and Aeta, and can even delay the fibrinolytic process in the AD mouse model; there is a higher burden of Abeta intra-parenchymal deposition in these mice, [195]. Many studies have focused on the data that HHcy can be considered a potential vascular risk factor [191, 192, 195], but final conclusions are still under debate. Homocysteine Studies Collaboration meta-analysis [196] suggests that HHcy can be considered an independent predictor of ischemic heart disease and stroke risk in healthy population


[196]. Another cross-sectional case-control study has been conducted in order to investigate the contribution of Hcy to cerebral white matter changes in patients with AD and controls [197]. Hcy has been considered a significant risk factor for the development of leukoaraoisis, comparable with age, systolic pressure, ApoE4 genotype and smoking [197]. Four years later, the conclusive results of HOPE 2 [198] demonstrated that a supplementary intake of folic acid, vitamin B6, and vitamin B12 decreased mean plasma homocysteine levels in patients with vascular disease and diabetes, but the decrease of Hcy did not interfere with death risk due to vascular pathologies or with a significant decrease in the prevention of new events [198]. Cochrane Database of Systematic Reviews [199] showed that Hcy lowering therapy did not reduce the incidence of myocardial infarction, stroke, or death by any vascular cause [199]. However, when considering the stroke incidence as an isolate event homocysteine-lowering therapy may relate to a reduction of stroke, like the one described in other studies [6, 55, 191, 192, 195, 199].

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The damage can be summarized as an altered regulation of the small arteries and an alteration of endothelium, principally related to a reduction in nitric oxide synthesis, involved in vessel autoregulation, and to a potentiation of atherothrombotic events [29, 193, 195]. CONCLUSION

Hcy remains, at the moment, a biological marker, with all its limits and without the key of solution for all the neuronal pathologies; EFSA [200] maintains a cautious position: it clearly stated that the maintenance of normal Hcy metabolism has a beneficial physiological effect. All the other protective, antioxidant, anti-inflammatory effects should be proven. Apart from the experimentally mediated suggestive role of reducing inflammation by diminishing Hcy, and the evidence of the indirect endothelium damage (mediated by H2S), there is a lack of other clinical evidence of benefits which has been obtained by reducing HHcy, contradicted by the brilliant results obtained in animal models or cells culture. To summarize, more and more evidence suggests that there should be a superimposition of microvascular damage in neurodegeneration by itself, and during ischemic events in the brain; in these conditions glutamate altered currents, NMDA receptor modifications and apoptosis occur simultaneously. So practically, the two processes (vascular and neurodegenerative) co-exist, at the same time, in probably different proportions, and it could be difficult to distinguish the effect of a compound, which might act on both the aspects. Large scale controlled studies are needed before a definite conclusion can be drawn.


HHcy due to inborn errors causes important and often fatal vascular pathologies [29, 194, 195]. There are strong studies which demonstrated that augmentation of Hcy is associated with increased cardio/cerebrovascular disease risk [6, 55, 191, 192, 195, 197]. However, in apparent contrast, no risk reduction has been found in homocysteine-lowering trials [7, 29, 196].

Moretti et al.

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Hcy remains a mystery: many experimental studies demonstrate, beyond any reasonable doubt, that Hcy has a causative role in the determination of neurological damages, due to its neurotoxic effect, to its direct or indirect vascular and endothelium induced pro-inflammatory effect. On the other hand, clinical studies have been inconclusive.

LIST OF ABBREVIATIONS AA

=

Amino Acids

A-B12

=

Adenosyl Cobalamine

AD

=

Alzheimer’s Disease

CBS

=

Cystathionine Synthase

FA

=

Fatty Acids

Hcy

=

Homcysteine

HHCY

=

Hyperhomcysteinemia

MAT

=

Methionine Adenosyl Trasnferase

M-B12

=

Methyl Cobalamine

Met-THF

=

Methylene-TetraHydroFolate

However, Hcy might be related to neurodegenerative disorders by potentiating the effects of Abeta deposition, augmenting its toxic effects, by modifying presenilin functions, and occasionally interfering with hyperphosphorylation of tau protein. On the other hand, it might also have a direct effect on smooth muscle vascular structures, potentiating the damage induced by Abeta deposition and activating caspase activity.

MMA-CoA =

Methtyl-malonyl Coenzyme A

MTHF

=

Methly-TetraHydroFolate

MTHFR

=

Methylene TetraHydroFolate Reducatse

MTR

=

Methionine Synthase

NTD

=

Neural Tube Defect

SAH

=

S-Adenosyl-L-Homocysteine=AdoHcy

Hcy is strenuously related to vascular risk factors, too. Hcy has been described as an independent risk factor for the development of many neurological vascular events, and recent data have demonstrated a reduction in stroke mortality, after folate fortifications. The association between hyperHCY and worsening of cognitive performance, Amyloid burden and white matter hyperintensities, has been confirmed in the majority the clinical studies considered.

SAM

=

S-Adenosyl-Methionine=AdoMet

S-CoA

=

Succinyl-CoA

THF

=

Tetrahydrofolate

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.


Current Nutrition & Food Science, 2017, Vol. 13, No. 3 [22]

ACKNOWLEDGEMENTS RM design and wrote the manuscript, analyzed the literature. MDB, SG and CT participated to the final writing and critically drafted the manuscript. MDB was supported by a U12GPFIRB11-CUP: J91J11000450001 fellowship.

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