Groundbreaking research led by the University of Alberta challenges the belief that mad cow disease is caused only by misfolded proteins - a discovery that sheds new light on the devastating outbreak in the United Kingdom 40 years ago and provides new hope for prevention.
The study shows for the first time that such prion-like brain diseases can be triggered without the presence of infectious prions. Prion disease occurs when normal proteins in the brain misfold into infectious, abnormal proteins.
Instead, chronic inflammation caused by a powerful bacterial endotoxin called lipopolysaccharide (LPS) was identified as a culprit that can independently trigger brain damage resembling prion disease.
"This fundamentally challenges the prevailing theory that these types of brain diseases are only about prions or similar misfolded proteins," says Burim Ametaj, a nutritional immunobiologist in the Faculty of Agricultural, Life & Environmental Sciences and lead author on the study.
(Photo: John Ulan)
The research revealed more of a multifaceted process behind that neurodegeneration, showing that inflammation weakens the brain's defences first, overwhelming cells. Proteins could then start misfolding and the immune system over-reacts, causing more damage.
"All three processes feed into each other, which means we need to target inflammation and immune health, not just the misfolded proteins."
New clue to a devastating outbreak
The discovery suggests that endotoxins in the animal-derived feed offered to cattle may have contributed to the bovine spongiform encephalopathy (BSE), or mad cow disease, crises in the United Kingdom, Ametaj says.
The outbreaks devastated the livestock industry in the 1980s and 1990s, resulting in the deaths of more than 160 people who'd eaten infected beef, and the slaughter of more than four million cattle.
The study provided striking evidence that LPS alone, administered under the skin, caused spongiform brain symptoms in 40 per cent of mouse models - a "holey" appearance in the tissues seen in BSE and related diseases. When LPS was combined with lab-created misfolded proteins, that number rose to 50 per cent. In both scenarios, this Alzheimer-like damage happened even when the naturally occurring infectious prion responsible for BSE was absent.
The research also showed that when an actual prion disease such as BSE is present, inflammation caused by LPS dramatically worsens damage to the brain, resulting in 100 per cent mortality within 200 days of infection.
The new findings could offer insight into why there were many more BSE cases in England and Wales than in Scotland, based on the procedures rendering plants used to make livestock feed, Ametaj says.
"Plants in England and Wales removed a critical substance called hexane from the production process to cut costs. This solvent was essential not only for fat extraction, but also for dissolving and removing LPS from the meat-and-bone meal.
"In contrast, Scottish rendering plants retained the hexane step and potentially because of that, had markedly fewer BSE cases - a fact long known but never systematically explained," he notes.
The study measured LPS in meat-and-bone meal, blood meal and tallow - the feed implicated in BSE - and confirmed high levels of contamination. Combined with chronic exposure to such feed, predisposing conditions in dairy cows induced by high-grain diets immediately postpartum, and by an increased "leaky gut", can trigger systemic inflammation and could contribute to the development of neurodegenerative disease, Ametaj notes.
"This suggests that excluding the hexane step left contaminated feed that could independently trigger neurodegeneration, explaining why the BSE epidemic followed the geographic pattern it did."
Implications for human diseases
The research may hold major implications for feed and livestock producers, Ametaj adds.
"The lessons from the BSE outbreaks about proper rendering processes and better feed safety remain relevant today. The prevention path is clear: maintain endotoxin-removal processing steps and monitor contamination. Any industrial feeding system that doesn't control this could create conditions for neurodegeneration."
He's also "cautiously optimistic" about how the findings could help prevent or treat human diseases such as Alzheimer's and Parkinson's.
"It opens up an entire anti-inflammatory medicine toolkit. Bacterial endotoxins have been found in the brains of Alzheimer's patients, so risk factors that reduce dementia - exercise, anti-inflammatory diets, gut health, metabolic health - might work partly by reducing endotoxin burden.
"These diseases are complex, but if endotoxin exposure contributes to even 20 to 30 per cent of cases, controlling this modifiable risk factor could spare millions of people," Ametaj adds. "We might prevent some neurodegenerative diseases the way we prevent heart disease, by managing inflammatory risk factors throughout life.
"In a field where there's been little hope, that matters."
Study co-authors include former master's student Seyed Ali Goldansaz, postdoctoral fellows Dagnachew Hailemariam and Elda Dervishi, U of A scientists David Wishart and David Westaway and his team, and researchers from the University of Warmia and Mazury in Poland.
The study was funded by the former Alberta Livestock and Meat Agency and the Alberta Prion Research Institute.
