The adverse effects of folate deficiency in the developing nervous system suggested the possibility that folate deficiency and elevated homocysteine levels might also have adverse effects in the adult nervous system.
Levels of homocysteine are increased in the cerebrospinal fluid of children with mutations in cystathioinine β-synthase and may contribute to the abnormalities in brain function documented in such patients.
Alzheimer's and Parkinson's diseases are two prominent age-related neurodegenerative disorders that affect millions of persons throughout the world.
Alzheimer's disease is believed to result from abnormal proteolytic processing of the amyloid precursor protein resulting in the production and accumulation of a neurotoxic self-aggregating 40-42 amino acid peptide called amyloid β-peptide.
Amyloid β -peptide promotes neuronal dysfunction and degeneration by inducing oxidative stress and disrupting cellular calcium homeostasis.
Neurons in brain regions involved in learning and memory are particularly vulnerable in Alzheimer's disease.
Transgenic mouse models that exhibit abnormalities in their brains that are similar to Alzheimer's patients have been produced by overexpressing mutated forms of amyloid precursor protein and a protein called presenilin-1.
In Parkinson's disease, neurons located in the substantia nigra selectively degenerate resulting in the inability to control body movements.
The affected neurons use dopamine as a neurotransmitter, and it is thought that these neurons are particularly susceptible to age-related increases in oxidative stress and to exposure to environmental toxins such as the pesticide rotenone.
Mouse and non-human primate models of Parkinson's disease have been developed in which toxins that selectively damage dopaminergic neurons are administered to the animals.
During the past decade data have accumulated that support roles for folate and homocysteine in modifying risk of Alzheimer's and Parkinson's diseases (Fig. 1).
Fig. 1. Examples of molecular cascades induced by homocysteine that can lead to cell dysfunction and/or death in cardiovascular disease, and Alzheimer's and Parkinson's diseases.
Alzheimer's patients have significantly lower levels of folate and higher levels of homocysteine in their blood when compared with neurologically normal agematched control patients.
Homocysteine levels are also elevated in patients with Parkinson's disease.
Interestingly, individuals with the C677T genotype, which results in elevated homocysteine levels, may be at increased risk of Parkinson's disease.
A weakness in the studies just described is that all analyses were performed on blood samples from symptomatic patients, and it is, therefore, unclear whether abnormalities in folate and homocysteine levels precede and contribute to the neurodegenerative process.
However, additional indirect evidence is consistent with a role for homocysteine in the disease process.
For example, age is the major risk factor for Alzheimer's and Parkinson's diseases, and studies have shown that homocysteine levels progressively increase with age.
Folate and vitamin B12 deficiencies may also contribute to the declines in cognitive and other neurological functions that occurs during usual aging.
In a study of over 100 geriatric patients admitted to a psychiatric hospital it was shown that individuals with below median values of folate and vitamin B12 performed worse on tests of cognitive function than did individuals with above-median levels of folate and vitamin B12.
Interestingly, elevated plasma homocysteine levels were not associated with cognitive impairment in centenarians.
Recent studies of cell culture and animal models of neurodegenerative disorders have provided evidence that folate deficiency and elevated homocysteine levels can indeed render neurons vulnerable to dysfunction and death.
Exposure of cultured rat hippocampal neurons to folate-deficient medium and homocysteine promotes apoptosis and increases the vulnerability of the neurons to being killed by amyloid β-peptide, a protein believed to be responsible for nerve cell death in Alzheimer's disease.
Transgenic mouse models of Alzheimer's disease have been established in which a mutated form of the amyloid precursor protein linked to familial Alzheimer's disease is overexpressed.
These mice exhibit a progressive age-dependent deposition of amyloid in their brains.
Maintenance of the Alzheimer's mice on a folate deficient diet results in degeneration of neurons in the hippocampus, a brain region with extensive amyloid deposition.
A mouse model of Parkinson's disease involves administration of a toxin called MPTP, which selectively damages dopaminergic neurons in the substantia nigra, a brain region that controls body movements.
Mice maintained on a folate-deficient diet or given homocysteine exhibit a marked increase in the sensitivity of their dopaminergic neurons to MPTP toxicity, which is reflected in severe motor dysfunction.
The specific mechanism whereby homocyteine endangers and kills neurons has recently been revealed.
An early and pivotal event in the adverse effects of homocysteine on neurons is increased DNA damage.
The DNA damage results from a combination of impaired DNA repair and increased oxidative stress, as indicated by increased uracil misincorporation and increased oxidative modification of DNA bases. DNA damage, in turn, triggers a cell death pathway involving poly (ADP-ribose) polymerase and the tumor suppressor protein p53, leading to mitochondrial dysfunction and activation of death proteases called caspases.
An important role for impaired DNA repair in the pathogenesis of Alzheimer's disease is suggested by a study documenting deficient repair of DNA lesions in fibroblasts from patients compared with agematched controls.
Homocysteine exacerbates oxidative stress, mitochondrial dysfunction and apoptosis in human dopaminergic cells exposed to the pesticide rotenone or the pro-oxidant Fe2+.
The adverse effects of homocysteine on dopaminergic cells is ameliorated by administration of the antioxidant uric acid and by an inhibitor of poly (ADP-ribose) polymerase.
The ability of folate deficiency and elevated homocysteine levels to sensitize dopaminergic neurons to environmental toxins suggests a mechanism whereby dietary folate may influence risk for PD.
Interestingly, alterations in folate and one-carbon metabolism may also contribute to several other neurodegenerative conditions.
For example, the huntingtin protein interacts with cystathionine β-synthase and alterations in folate metabolism have been documented in patients with amyotrophic lateral sclerosis.
Homocysteine can induce seizures in rodents and alterations in homocysteine levels may occur in human epilepsy patients suggesting a possible contribution to epilepsy.
Amyotrophic lateral sclerosis (ALS) is an age-related disorder in which spinal cord motor neurons degenerate resulting in progressive paralysis and death.
It has been proposed that an abnormality in folate metabolism accounts for the reported reduction of RNA and the elevation of taurine in the nervous system of ALS patients.
Talking about other age related diseases, homocysteine levels are often elevated in patients with type 2 diabetes and, although it has not been clearly established that homocysteine plays a key role in the disease onset, there is considerable evidence that it contributes to major complications in this disease.
For example, homocysteine is independently associated with the prevalence of diabetic neuropathy in patients with type 2 diabetes, suggesting that folate supplementation may reduce the extent of involvement of the nervous system in patients with diabetes.
Patients with rheumatoid arthritis have elevated homocysteine levels, although it remains to be established if and how homocysteine participates in the pathogenesis of this disorder.
Homocyteine can promote increased blood coagulation, which may increase risk of a variety of vascular events in various organs by impairing the conversion of fibrinogen to fibrin by thrombin, homocysteine can induce platelet aggregation.
As can be appreciated from literature, elevated homocsyteine levels are associated with a broad array of age-related diseases.
There are a number of approaches that can be taken to lower homocysteine levels and that would, therefore, be expected to reduce risk of various disorders during aging.
The major approach already in use is dietary supplementation with folate (typically 400 μg per day).
Dietary supplementation with vitamins B12 and B6 can also lower homocysteine levels, and may enhance the effect of folate.
Dietary restriction, a manipulation that can extend lifespan and reduce incidence of many different age-related diseases, may also lower homocysteine levels.
It has also been reported that vegetarian diets and physical exercise can decrease homocysteine levels.
The extent to which decreased homocysteine levels contributes to the beneficial effects of these various dietary and lifestyle manipulations during aging remains to be established.
However, the emerging experimental findings, do suggest cellular and molecular mechanisms, whereby homocysteine may accelerate age-related dysfunction and damage to various cell types.