On 30 September, Dr Alessandra Cadete Martini and colleagues published a paper in PNAS identifying a new regulator of neuroinflammation in Alzheimer’s disease, TOM1. Chronic inflammation is a feature of many age-related neurodegenerative diseases. In Alzheimer’s disease (AD), research has shown that several immune pathways are hyperactivated, causing cognitive dysfunction by prolonging inflammation. In young individuals, however, these immune pathways retain the ability to “switch off”; as a result, inflammation is swiftly limited and resolved. The TOM1 protein, which sits on the surface of recycling structures called “endosomes”, can bind to inflammatory receptors that activate immune pathways. In doing so, the cellular waste disposal machinery is activated: TOM1 pulls the inflammatory receptors into endosomes, ensuring they are broken down and eliminated. TOM1 therefore plays an important role in the resolution of inflammation in healthy individuals, helping our immune systems to “switch off” when they are no longer required. However, the role of TOM1 during the development of AD is not yet fully understood.
To address this question, Dr Cadete Martini and colleagues studied tissues and cells from people with AD as well as mouse models of disease, aiming to identify whether TOM1 could represent a therapeutic target. TOM1 was significantly reduced in brain samples from people with AD, which showed a corresponding increase in IL1R1, an inflammatory receptor. The researchers showed that this was directly linked to amyloid accumulation, as neurons treated with pathological amyloid proteins expressed more IL1R1 and less TOM1. When they disrupted TOM1 in animal models of AD, researchers observed a substantial increase in brain inflammation: microglia were less able to disperse and phagocytose harmful amyloid proteins, resulting in more amyloid plaque formation. Interestingly, the resultant cognitive decline was not observed in animals treated with a gene therapy virus that increases TOM1. Together, these results suggest that reduced TOM1 in AD promotes neuroinflammation and contributes to amyloid plaque formation.