Researchers here provide evidence for lower levels of TOM1 observed in Alzheimer's disease to be a proximate cause of chronic inflammation in the brain, and suggest that therapies to raise TOM1 levels might dampen inflammation to a great enough degree to be useful to patients. The inflammation and disarray in the brain's immune system, particularly microglia, is implicated in a range of neurodegenerative conditions. In the case of Alzheimer's disease it remains debatable as to where neuroinflammation sits in the chain of cause and consequence: is it a result of amyloid-β aggregation, a necessary step that leads to the much more harmful tau aggregation that characterizes the later stages of the condition, or does it also directly cause amyloid-β aggregation? Both might be the case - there are a great many two-way interactions in aging.
As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses, and the chronic inflammation mediated by inflammatory receptors represents a key mechanism by which amyloid-beta (Aβ) drives the development of cognitive decline in Alzheimer's disease (AD). A crucial aspect of this process is a failure to resolve inflammation, which involves the suppression of inflammatory cell influx and the endocytosis of inflammatory receptors.
To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic.
This data shows that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.