Homocysteine and Alzheimer's disease

doi:10.1016/S1474-4422(03)00438-1

The Lancet Neurology

Volume 2, Issue 7, July 2003, Pages 425-428

https://doi.org/10.1016/S1474-4422(03)00438-1 Get rights and content

Summary

Background

A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer's disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible.

Recent developments

A recent prospective study (S Seshadri and colleagues N Engl J Med; 2002 346: 476–83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification.

Where next?

25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.

Section snippets

Recent epidemiological studies of homocysteine and AD

A study of 43 volunteers diagnosed with probable or possible AD and 37 controls from the same population of outpatients suggested that hyperhomocysteinaemia was not related to AD.¹⁶ Any apparent link was explained by the coexistence of the AD and vascular disease. Nevertheless, after accounting for history of clinically evident vascular events, the patients with AD in this small study were more than twice as likely as controls to be hyperhomocysteinaemic, and the confidence interval for the

Studies of homocysteine and early temporal-lobe changes

An investigation prompted by the finding of a relation between atrophy of the temporal medial lobe and hyperhomocysteinaemia in AD sought to determine whether hippocampal width, which is known to decrease with age, was related to plasma concentrations of homocysteine in community-dwelling elderly people.²² The individuals had no clinical memory problems, and cognitive function tests were used to screen out volunteers with mental impairment. The study found that hippocampal width decreased

Possible mechanisms for the association between hyperhomocysteinaemia and AD

The Nun Study,²⁴ a longitudinal study of ageing and AD, found that dementia was worse in the presence of brain infarcts, therefore, hyperhomocysteinaemia may contribute to AD dementia by induction of vascular changes. However, homocysteine was directly excitotoxic to cortical neurons in cell culture, which suggests a causal role for the amino acid in the cholinergic deficit characteristic of AD.²⁵ Alternatively, neuronal death through apoptosis could result from folate deficiency via

Conclusion

An association between hyperhomocysteinaemia and AD is well established. Furthermore, the follow-up study by Seshadri and colleagues⁸ showed that high homocysteine concentration preceded the diagnosis of AD. Because the diagnosis would likely have been made long after disease onset, reverse causation might seem plausible. However, homocysteine measurements taken 8 years earlier in a subset of patients gave similar results. Studies relating changes in the temporal lobe to hyperhomocysteinaemia

References (33)

RiggsKM et al.
Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study
Am J Clin Nutr
(1996)
RavagliaG et al.
Homocysteine and cognitive function in healthy elderly community dwellers in Italy
Am J Clin Nutr
(2003)
MorrisMS et al.
Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey
Am J Clin Nutr
(2001)
BurnsA et al.
Mild cognitive impairment in older people
Lancet
(2002)
MattsonMP et al.
Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders
Trends Neurosci
(2003)
McCaddonA et al.
Alzheimer's disease and total plasma aminothiols
Biol Psychiatry
(2003)
BousheyCJ et al.
A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes
JAMA
(1995)
RefsumH et al.
Homocysteine and cardiovascular disease
Annu Rev Med
(1998)
NilssonK et al.
Hyperhomocysteinaemia: a common finding in a psychogeriatric population
Eur J Clin Invest
(1996)
BellIR et al.
Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people
Acta Psychiatr Scand
(1992)

LeblhuberF et al.

Hyperhomocysteinemia in dementia

J Neural Transm

(2000)

GottfriesCG et al.

Early diagnosis of cognitive impairment in the elderly with the focus on Alzheimer's disease

J Neural Transm

(1998)

McCaddonA et al.

Total serum homocysteine in senile dementia of Alzheimer type

Int J Geriatr Psychiatry

(1998)

SeshadriS et al.

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N Engl J Med

(2002)

McIlroySP et al.

Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland

Stroke

(2002)

BudgeMM et al.

Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people

J Am Geriatr Soc

(2002)

Cited by (335)

Betaine alleviates cognitive impairment induced by homocysteine through attenuating NLRP3-mediated microglial pyroptosis in an m<sup>6</sup>A-YTHDF2-dependent manner
2024, Redox Biology
Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 μg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1β, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1β. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N⁶-methyladenosine (m⁶A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m⁶A reader YTH N⁶-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m⁶A-YTHDF2-dependent manner.
Rational design of dual-channel response fluorescent probe and its application for highly efficient biothiols imaging in living samples
2024, Journal of Photochemistry and Photobiology A: Chemistry
Biothiols have the function of maintaining redox balance in organisms and play critical roles in human pathophysiology. This work reported a highly sensitive dual-channel responsive fluorescent probe SKY-NBD utilized for the detection of biothiols in vitro and in vivo. By incorporating the NBD-Cl with the other fluorophore dihydrocyclopentachromene derivative (SKY-OH), the sensitive probe was successfully formulated. Ascribe to the strong electron-withdrawing effect of NBD group, SKY-NBD had almost no fluorescence. Afterwards the supplement of Cys or Hcy, SKY-NBD rapidly gave significantly fluorescent enhancement in both the red and green channels, which was attributed to the release of fluorescent groups SKY-OH and amine-substituted NBD (NBD-NR). However, upon exposure to GSH, only a strong red-channel emission established, revealing the release of SKY-OH. Subsequently, the SKY-NBD probe was effectively utilized for high-quality image of biological thiols in living cell and zebrafish larva. Compared with other NBD-Cl probes, SKY-NBD achieved highly sensitive dual-channel detection of biothiols. Heretofore, we had successfully erected a dual-channel responsive fluorescent probe for the recognition of biothiols. The probe SKY-NBD holds great potential for studying biothiol-related diseases in living system.
Integrative metabolomics science in Alzheimer's disease: Relevance and future perspectives
2023, Ageing Research Reviews
Alzheimer’s disease (AD) is determined by various pathophysiological mechanisms starting 10–25 years before the onset of clinical symptoms. As multiple functionally interconnected molecular/cellular pathways appear disrupted in AD, the exploitation of high-throughput unbiased omics sciences is critical to elucidating the precise pathogenesis of AD. Among different omics, metabolomics is a fast-growing discipline allowing for the simultaneous detection and quantification of hundreds/thousands of perturbed metabolites in tissues or biofluids, reproducing the fluctuations of multiple networks affected by a disease. Here, we seek to critically depict the main metabolomics methodologies with the aim of identifying new potential AD biomarkers and further elucidating AD pathophysiological mechanisms. From a systems biology perspective, as metabolic alterations can occur before the development of clinical signs, metabolomics – coupled with existing accessible biomarkers used for AD screening and diagnosis – can support early disease diagnosis and help develop individualized treatment plans. Presently, the majority of metabolomic analyses emphasized that lipid metabolism is the most consistently altered pathway in AD pathogenesis. The possibility that metabolomics may reveal crucial steps in AD pathogenesis is undermined by the difficulty in discriminating between the causal or epiphenomenal or compensatory nature of metabolic findings.
An off-on quinoxaline-based fluorescent probe for lighting up biothiols in living cells and zebrafish
2023, Tetrahedron
A novel fused four-ring quinoxaline fluorophore and a maleimide receptor were firstly integrated into one molecule to develop a novel, sensitive and highly effective probe for biothiols detection. The fluorescence of quinoxaline fluorophore was quenched by the maleimide group via the photoinduced electron transfer (PET) mechanism. After the Michael addition of the biothiols towards maleimide, the PET process was blocked and the fluorescence restored. The above sensing mechanisms were confirmed by the mass spectroscopy and explained by density functional theory (DFT) calculations, ensuring QX9M as a highly selective probe towards biothiols over other amino acids. Moreover, the probe featured a good linearity range and a low detection limit to Cys, Hcy and GSH. For the practical applications, the probe can be used to monitor the biothiols not only in living cells but also in zebrafish with an off-on process.
Epigenetic regulons in Alzheimer's disease
2023, Progress in Molecular Biology and Translational Science
Alzheimer's disease is one of the most prevalent forms of dementia that occur genetically or sporadically (with increasing age) in the population of 65 years and above. The pathological hallmarks of AD include the formation of extracellular senile plaques of amyloid beta peptides 42 (Aβ₄₂) and intracellular neurofibrillary tangles associated with hyperphosphorylated tau protein. AD has been reported as an outcome of multiple probabilistic factors such as age, lifestyle, oxidative stress, inflammation, insulin resistance, mitochondrial dysfunction, and epigenetics. Epigenetics are heritable changes in gene expression that give a phenotype without altering the DNA sequences. Epigenetic mechanisms include DNA methylation, hydroxymethylation, histone modifications, regulation of miRNAs and long non-coding RNAs, which are reported to be dysregulated in AD. Further, epigenetic mechanisms have been shown as a key player as they regulate memory development, where DNA methylation and post-translational modifications of histone tails are the prime epigenetic markers. Also, alterations of AD-related genes cause pathogenesis on the transcriptional level. In the current chapter, we summarize the role of epigenetics in the onset and progression of AD and the use of epigenetic therapeutics to ameliorate the constraints of AD.
Screening, characterization and anti-cancer application of purified intracellular MGL
2022, International Journal of Biological Macromolecules
L-methionine-γ-lyase (MGL) producing bacterial isolates were screened from soil samples that further characterized as ‘Klebsiella oxytoca BLM-1’ by biochemical and 16S rDNA sequencing. Intracellular MGL obtained from K. oxytoca BLM-1 by sonication was purified by Octyl-Sepharose and Sephadex G-200 column chromatography. MALDI-TOF-MS analysis of protein band (Mr ~ 63 kDa) confirmed the PLP-dependence and structural similarity with MGL enzyme. Purified MGL (1.1 μg) exhibited the maximum activity in potassium phosphate buffer (80 mM; with L-met 20 mM pH 7.0) at 37 °C. That further enhanced in the presence of NaCl (2 mM), Tween-80 (1.0 %; v/v) and EDTA (5 mM). K_m and V_max for purified MGL by using L-met as substrate was found to be 5.32 mM and 0.386 U/mL/min. The purified MGL showed PLP dependence and the half-life was 365.59 min. The MGL was effective against breast cancer (MCF7), gastric adenocarcinoma and human glioblastoma (U87MG) cancer cell lines with IC₅₀ values of purified MGL 0.041 U/mL, 0.008 U/mL and 0.009 U/mL, respectively. The U87MG, greatly affected by MGL treatment, when cultured in DMEM medium (10 mL) with PLP, homocysteine and 10 % FCS as compared to control/untransformed mouse spleen cells.

View all citing articles on Scopus

View full text

Rapid ReviewHomocysteine and Alzheimer's disease

Summary

Background

Recent developments

Where next?

Section snippets

Recent epidemiological studies of homocysteine and AD

Studies of homocysteine and early temporal-lobe changes

Possible mechanisms for the association between hyperhomocysteinaemia and AD

Conclusion

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Lancet

Trends Neurosci

Biol Psychiatry

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes

JAMA

Homocysteine and cardiovascular disease

Annu Rev Med

Hyperhomocysteinaemia: a common finding in a psychogeriatric population

Eur J Clin Invest

Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people

Acta Psychiatr Scand

Hyperhomocysteinemia in dementia

J Neural Transm

Early diagnosis of cognitive impairment in the elderly with the focus on Alzheimer's disease

J Neural Transm

Total serum homocysteine in senile dementia of Alzheimer type

Int J Geriatr Psychiatry

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N Engl J Med

Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland

Stroke

Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people

J Am Geriatr Soc

Rapid Review
Homocysteine and Alzheimer's disease