Untangling Inflammation-Causing Factors in Alzheimer’s

Amyloid plaques and tau protein tangles are well-known Alzheimer’s disease buzzwords, but the reality is that these factors alone generally do not result in disease. Instead, it is the neuroinflammation that occurs in response to these plaques and tangles that cause death of neurons and cognitive decline. New details of how this inflammation occurs and potential clues to preventing brain tissue inflammation connected to Alzheimer’s disease (AD), were recently presented in the journal Neuron.

The study was done by scientists working in the Tanzi lab at Massachusetts General Hospital—this was the same lab that had discovered the first gene associated with AD-related neuroinflammation back in 2008. The gene is known as CD33, and is involved in clearing away neurological debris. When the gene is highly expressed, it can turn into a neuron killer, driving neuroinflammation.

The current study focused on the interaction of CD33 and another AD-associated gene called TREM2. TREM2 has the opposite effect of CD33, shutting down microglia’s ability to promote neuroinflammation.

To do this, the researchers set up an experiment in which the two genes were silenced in both individually and simultaneously in a mouse model of AD. Those with CD33 turned off had reduced levels of amyloid plaques and performed better on cognitive tests. Those with both CD33 and TREM2 turned off had similar benefits. On the other hand, those that had only the TREM2 gene silenced did not have any benefits. These results indicate that TREM2 works downstream of CD33. Sequencing of microglia RNA further supported this theory, indicating both CD33 and TREM2 modulate an immune cell called IL-1 beta and the receptor Il-1RN.

These findings could facilitate development of therapeutics that target these two receptors.