Slowing the progression of Alzheimer’s
Microglia are a group of immune cells of the central nervous system. They act as a link between the nervous and immune systems. They scan their surroundings in the intact brain, where they eliminate waste products, damaged cells, and infectious agents. Microglial cells play an important role in the context of neurological diseases and the development of Alzheimer’s, mediating a wide range of mechanisms. It has long been known that they can be activated in different ways in Alzheimer’s, Parkinson’s and other diseases. The crux, however, is that depending on how they are activated, they can both drive and slow disease development.
Now, a new study published Nov. 28 in Nature Aging shows that microglial cells can be activated in a specific way to trigger inflammatory protective mechanisms in the immune system.
The connection between TREM2 and microglia
One of the proteins that clings to the surface of microglial cells is called TREM2 (Triggering Receptor Expressed On Myeloid Cells 2). When loss-of-function mutation occurs in the TREM2 gene, which encodes the microglia protein, the risk of developing Alzheimer’s increases. However, when the protein is functional and activated, it can be protective instead. Microglial cells help track down residual products of decaying cells in the brain. They eat up so-called tau proteins, which are responsible for the filamentous structures and the formation of deposits.
However, as for the effects of microglial activation on future tau deposition in humans, there have been conflicting results. So, researchers decided to investigate the role of microglia in tau accumulation in the early stages of the disease. Therefore, they measured various microglia markers in nondemented individuals. Their aim was to identify new biomarkers for the diagnosis of AD at an early stage, when it can still be treated.
Here, we measured the microglial marker soluble TREM2 and the disease-associated microglial activation stage 2 markers AXL, MERTK, GAS6, LPL, CST7, SPP1 and CSF1 in nondemented individuals (…). To assess whether baseline microglial markers had an effect on AD-related changes, we studied three sub-groups of individuals: 121 with evidence of amyloid-PET pathology (A+), 64 with additional evidence of tau-PET pathology (A+T+) and 159 without amyloid- or tau-PET pathology (A−T−).
Microglia can ingest damaged cells in the brain, prevent the formation of deposits and slows cognitive decline
The study included 387 nondemented individuals and followed 64 people with evidence of tau pathological changes who had not yet developed symptoms of Alzheimer’s disease. The researchers found that the patients who had higher TREM2 levels at the start of the study had fewer deposits in their brains and less cognitive decline a few years later.
This shows that when the TREM2 receptor on microglia can detect the presence of damaged brain cells at an early stage of the disease, they can protect against tau accumulation.
Our results showed that increased levels of TREM2 were associated with slower amyloid accumulation in A+ individuals in addition to slower tau deposition and cognitive decline in A+T+ subjects. Similarly, higher levels of AXL, MERTK, GAS6, LPL, CST7 and CSF1 predicted slower tau accumulation and/or cognitive decline in the A+T+ group. These findings have important implications for future therapeutic strategies aiming to boost microglial protective functions in AD.