A bold warning: brain damage can look like prion disease even when infectious prions aren’t present. New findings suggest the role of misfolded proteins may be less singular than once thought, and inflammation might be a driving force behind several neurodegenerative conditions.
Prions are infamous for their connection to diseases such as mad cow disease, chronic wasting disease in deer, and Creutzfeldt-Jakob disease in humans. Recent mouse research shows that brain features typical of prion disease — sponge-like holes, scarring, and amyloid plaques — can develop without infectious prions in their disease-causing form.
Instead, researchers found that non-infectious prion precursors, when paired with chronic inflammation triggered by a bacterial endotoxin, were enough to spark prion-like degeneration in the brain. This shifts the spotlight from prions alone to the combination of inflammatory processes and misfolded proteins, uncovering a broader set of mechanisms that could underlie prion diseases and related disorders.
This has significant implications for prion-like conditions such as Alzheimer’s, Parkinson’s, and ALS, where misfolded proteins play a central role in irreversible brain damage. Prion diseases in humans occur when normal biological processes go awry in rare cases, producing proteins that misfold and then coerce others to misfold as well, while resisting the body’s cleanup systems.
Proteins normally fold into shapes that support their functions. Most misfolded proteins are managed and destroyed by cellular quality-control systems. But some misfolded proteins become prions, which not only malfunction themselves but also propagate their abnormal shape to other proteins. The result can be a cascading failure of cellular function. Prions are inherently infectious, capable of spreading between individuals, often via contaminated food.
Prion-forming proteins are known as PrPC. A misfolded PrPC doesn’t automatically become an infectious prion; that particular misfolding is a more specific, infectious pathway. Emerging evidence, however, indicates that other routes of PrPC misfolding may also contribute to neurodegeneration, even if they don’t create infectious prions.
Another line of evidence points to lipopolysaccharide (LPS) — a bacterial endotoxin found on some bacteria’s outer membranes — as a potential accelerator of prion diseases. LPS can promote protease resistance in prion proteins and heighten inflammation, both of which may worsen neuronal damage.
In a study led by immunologist Burim Ametaj at the University of Alberta, transgenic mice were used to parse the roles of non-infectious prion forms and chronic inflammation in prion-like brain degeneration. Researchers engineered a misfolded PrP form toxic to neurons but not infectious.
Mice were divided into six groups: saline control; LPS alone; non-infectious misfolded PrP alone; misfolded PrP with LPS; infectious prions alone; infectious prions with LPS. They were observed for up to 750 days, examining brain changes such as sponge-like damage, protease resistance, astrogliosis (scarring), and amyloid plaques — all features associated with prion disease.
Key observations included: misfolded, non-infectious PrP alone caused sponge-like damage and scarring without protease resistance; LPS alone produced amyloid plaques and spongiform damage with a notable 40% mortality but no protease resistance. The combination of LPS with non-infectious PrP worsened brain holes, while the trio of prions with LPS dramatically accelerated disease progression, with all such mice dying within about 200 days.
These results challenge the idea that prion diseases arise solely from prions or similar misfolded proteins. They suggest that inflammation may weaken the host first, allowing misfolded PrP to drive degeneration, or even that non-infectious PrP misfolding could initiate the cascade leading to prion formation.
The research also ties into Alzheimer’s-like outcomes seen in mice exposed only to LPS, underscoring the potential importance of inflammation in starting prion-like neurodegenerative processes. This aligns with growing evidence linking inflammation to Alzheimer’s disease and related conditions.
The researchers emphasize a potential shift in therapeutic strategy: reducing inflammation could be a powerful tool against neurodegenerative risk. Since endotoxin exposure and inflammatory states are modifiable through lifestyle choices — such as regular exercise, anti-inflammatory diets, gut health, and metabolic management — preventing dementia might become more achievable by targeting inflammatory risk factors throughout life.
If endotoxin-related pathways contribute to even a portion of neurodegenerative cases, addressing this modifiable risk could spare millions from suffering. In a field often marked by limited hope, these findings offer a promising new angle for prevention and treatment.
The study is published in the International Journal of Molecular Sciences.
