Nav: Home

Elevated homocysteine identified as metabolic risk factor for neurodegenerative diseases

May 16, 2018

(Philadelphia, PA) - The amino acid homocysteine occurs naturally in the human body, generated as a byproduct of methionine metabolism. Genetic diseases or an imbalanced diet, with too much red meat or deficiencies in B vitamins and folic acid, however, can lead to high homocysteine levels, a condition known as hyperhomocysteinemia. This condition causes considerable harm to the heart but can also affect the brain.

Now, in a new study published online in the journal Molecular Psychiatry, researchers at the Lewis Katz School of Medicine at Temple University further reveal the extent to which elevated homocysteine damages the brain. In mice, they show that diet-induced increases in homocysteine levels directly contribute to the development of damaging neurofibrillary tangles, which result from the progressive accumulation of abnormal tau protein in the brain. Tau neurofibrillary tangle accumulation is a major contributor to nerve cell death, dementia, and neurodegenerative disease.

"Abnormal tau is responsible for the formation of neurofibrillary tangles in the brain of Alzheimer's disease and other forms of dementia," explained Domenico Praticò, MD, Scott Richards North Star Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine at Temple University (LKSOM), and senior investigator on the new report. "From previous research we knew that hyperhomocysteinemia is a risk factor for Alzheimer's disease, affecting memory and the formation of harmful amyloid beta plaques in the brain. However, it was unclear whether it also influenced tau neurofibrillary tangle formation, which is the second-most important brain lesion in Alzheimer's disease, in addition to amyloid plaques."

To explore this question, Dr. Praticò and colleagues used a dietary approach in mice, inducing an increase in homocysteine levels by implementing a diet deficient in folic acid and vitamins B6 and B12. The researchers specifically used mice engineered to develop only tau tangles, with no amyloid plaque formation, enabling them to investigate a possible direct effect of homocysteine on the development of tau lesions.

Starting at four months of age, tau mice were put on the vitamin-deficient diet. Eight months later, the animals were tested in their learning and memory abilities in a water maze test. Compared with control tau mice, which ate a regular diet throughout the study, tau mice on the vitamin-deficient diet performed significantly worse, showing impairments in learning a new task and, most importantly, in their ability to remember the task.

To better understand why, the researchers examined brain tissues from both groups of mice. "We observed that the brains of the animals receiving the deficient diet had not only increased homocysteine levels but also a 50 percent increase in the amount of tau tangles in the hippocampus and cortex, relative to control animals," Dr. Praticò said. Levels of insoluble, toxic tau protein, which causes neuron death, were also elevated, and cells exhibited disruption in the integrity of their synapses, the junctions between neurons that allow the cells to communicate.

Dr. Praticò's team further discovered that one of the earliest changes that the elevated homocysteine levels induced in the brain is the activation of a protein called 5-lipoxygenase (5LO). By controlling the cdk5 enzyme, 5LO is ultimately responsible for the formation of abnormal tau and the development of tau tangles.

According to Dr. Praticò, the next step is to find out whether the damage caused by high homocysteine and mediated by 5LO can be blocked. "Now that we know for the first time that homocysteine acts via 5LO to induce the abnormal tau tangle formation and nerve cell death, next we can test whether blocking 5LO can prevent the brain damage secondary to high homocysteine," he said. His team is also interested in testing whether 5LO blockade can reverse homocysteine-induced nerve cell damage after it has been established.
-end-
Other researchers contributing to the study include Antonio Di Meco and Jian-Guo Li at the Alzheimer's Center at Temple, LKSOM; and Carlos Barrero and Salim Merali in the Department of Pharmaceutical Sciences, Temple University.

The research was funded in part by National Institutes of Health grants HL112966 and AG51684.

About Temple Health

Temple University Health System (TUHS) is a $2.1 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University, and Temple University Physicians, which is Temple Health's physician practice plan comprised of more than 500 full-time and part-time academic physicians in 20 clinical departments.

The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.

Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.

Temple University Health System

Related Folic Acid Articles:

Hypertensive patients may benefit from folic acid supplements
Hypertensive adults with low platelet count who took a combined daily pill of both enalapril and folic acid saw a 73 percent reduction in their risk of first stroke compared to patients who took only enalapril daily, according to a study published in the Journal of the American College of Cardiology.
Formate prevents most folic acid-resistant neural tube defects in mice
A multi-institutional research team has developed a novel folic acid-resistant neural tube defect mouse model of the human condition by silencing the Slc25a32 gene, and, in most of the mutant mice, neural tube defects can be prevented by formate supplementation.
Folic acid late in pregnancy may increase childhood allergy risk
Research from the University of Adelaide suggests that taking folic acid in late pregnancy may increase the risk of allergies in children affected by growth restriction during pregnancy.
Folic acid may mitigate autism risk from pesticides
Researchers at UC Davis and other institutions have shown that mothers who take recommended amounts of folic acid around conception might reduce their children's pesticide-related autism risk.
Psychological benefits for kids when mums keep taking folic acid
Taking folic acid supplements throughout pregnancy may improve psychological development in children.
Folic acid supplementation recommended for prevention of neural tube defects
The US Preventive Services Task Force recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid.
Daily folic acid supplementation remains important for prevention of birth defects
Despite the mandatory addition of folic acid to enriched grain products in the United States, many women still do not consume adequate amounts of this important vitamin, according to an editorial written by Laura E.
Folic acid fortified food linked to decline in congenital heart defects
Food fortified with folic acid helped lower overall rates of congenital heart defects in Canada.
Less decline than expected in brain, spine defects after folic acid fortification program
There is less decline than expected in the rate of brain and spine defects after a folic acid fortification program, a Stanford study finds.
Putting the spotlight on folic acid supplementation in pregnancy
Future Science Group today announced the publication of a new article in Future Science OA, reviewing national and international guidelines for folic acid supplementation, and analyzing its potential risks and benefits in terms of maternal and fetal outcomes.
More Folic Acid News and Folic Acid Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.