Monkeys on Neurotoxic Diet May Be New Animal Model for ALS Research

A neurotoxic amino acid called β-N-methylamino-L-alanine (BMAA) fed to vervet monkeys caused damage to the spinal cord similar to what is seen in amyotrophic lateral sclerosis (ALS), potentially making them a much-needed new animal model for research, a study reported.

Adding L-serine, a non-toxic amino acid, to their diet also eased the damage.

The study, “L-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND,” was published in the Journal of Neuropathology & Experimental Neurology.

BMAA is a cyanobacterial neurotoxic amino acid, meaning it is produced by certain kinds of bacteria, particularly blue-green algae blooms. It was first discovered as the likely cause of Guam ALS/Parkinsonism dementia complex (PDC), an ALS-like condition seen in the Chamorro people, who are indigenous to the Mariana Islands.

This toxic amino acid has also been found in brain tissue of people with ALS and Alzheimer’s disease living in North America.

While there’s not enough data to suggest BMAA is the cause of ALS – indeed, the causes of ALS are likely multifactorial, including both genetic and environmental factors — the discovery of this toxin may have useful research applications.

Currently, ALS animal models rely almost exclusively on inducing genetic mutations known to cause this disease. But the vast majority of ALS patients have no clear disease-causing mutations. BMAA could be used to develop an ALS animal model that better matches the patient population, and might include “the neuropathological changes that occur in presymptomatic individuals,” the scientists wrote.

Some of these researchers had previously demonstrated that adding BMAA to the diet of vervet monkeys led to ALS-like changes in the brain. In this study, a team led by Miller School of Medicine, University of Miami scientists examined whether such changes also occur in the spinal cord.

Monkeys were given one of three diets: a control diet, a diet with BMAA added, and a diet with both BMAA and L-serine. L-serine is a natural, dietary amino acid shown to be beneficial in some models of neurological disease.

After feeding the monkeys for 140 days, the researchers examined cells in their spinal cords. For reference, they also looked at samples from a person, a 58-year-old Caucasian male, who had died of ALS.

The spinal cords of BMAA-fed monkeys had numerous features comparable to ALS. For instance, there were significantly fewer motor neurons, and those that were present were smaller, indicative of motor nerve cell death. Their motor neurons were also found to contain Bunina bodies, formations characteristic of ALS. Aggregates containing the ALS-associated proteins TDP-43 and UBIQ were also seen.

“The presence of both TDP-43+ and UBIQ+ protein inclusions along with Bunina bodies in [spinal cord] neurons suggests that chronic BMAA dosing causes motor neuron injury in vervets characteristic of ALS,” the researchers wrote.

BMAA administration also caused ALS-like changes in astroglia, nervous system cells that support neuronal function, and led to ALS-like activation of microglia, immune cells in the nervous system that can drive inflammatory responses.

“These data suggest that BMAA-exposed vervets may serve as a useful experimental model for testing novel therapeutics for the treatment of ALS,” the researchers wrote. The Brain Chemistry Labs, a non-profit research organization whose scientists took part in the study, has a patent pending on this animal model.

In monkeys co-treated with L-serine, significant reductions in the number of ALS-associated protein aggregates called neurofibrillary tangles were evident, as well as a lesser pathological activation of astroglia and microglia.

“Our results provide preclinical evidence of the efficacy of L-serine,” the researchers wrote.

Adding L-serine to their diet did not lower the amount of BMAA in the monkeys’ spinal cords, or reduce the toxic incorporation of BMAA into proteins. As such, it is not clear what mechanism L-serine uses to confer the benefits seen; more research will be needed in this regard.

It is also important to note that positive results in animal models are no assurance that similar effects might be seen in people.

“While these data provide valuable insights, we do not yet know if L-serine will improve outcomes for human patients with ALS,” Walter Bradley, DM, a study co-author and professor at the University of Miami, said in a press release. “We need to carefully continue FDA-approved clinical trials before we can recommend that L-serine be added to the neurologists’ toolbox for the treatment of ALS.”

L-serine as an oral supplement is currently being investigated in a Phase 2 trial (NCT03580616) of adults with ALS. The trial is enrolling up to 50 eligible patients at Dartmouth-Hitchcock Medical Center in New Hampshire; more information can be found here.