Researchers have identified TREM2 as a target to potentially enhance the ability of immune cells in the brain to remove amyloid beta, solid deposits of misfolded proteins associated with the progression of Alzheimer's disease. Removal of amyloid beta remains the primary focus of the Alzheimer's research community, despite the continued lack of progress towards working therapies based on this approach. An increasing number of researchers are investigating alternatives to the existing approaches to amyloid immunotherapy, so far failing to achieve meaningful results in human trials.
The slow accumulation of amyloid beta and other metabolic waste in the brain looks a lot like the consequence of a slow failure of clearance mechanisms, as amyloid levels are actually quite dynamic from moment to moment. One candidate for this failure is the age-related deterioration of immune activity, in and of itself a very complex topic - which is one reason to think that therapies based on improved immune function might be helpful. Other candidates include failure of filtration of cerebrospinal fluid in the choroid plexus, or more recent views on the failure of cerebrospinal fluid drainage. Alzheimer's is a complex condition, and the brain is a complex organ.
Two new studies describe how TREM2, a receptor found on immune cells in the brain, interacts with toxic amyloid beta proteins to restore neurological function. The research, performed on mouse models of Alzheimer's disease, suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders including Alzheimer's disease. "Our first paper identifies how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer's disease pathogenesis. The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms."
One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques that form between neurons and interfere with brain function. Many drug companies have been working for years to reduce amyloid beta production to thwart Alzheimer's - but with minimal success. "TREM2 offers a potential new strategy. Researchers have known that mutations in TREM2 significantly increase Alzheimer's risk, indicating a fundamental role for this particular receptor in protecting the brain. This new research reveals specific details about how TREM2 works, and supports future therapeutic strategies to strengthen the link between amyloid beta and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease."
The first study showed that TREM2 binds quite specifically to amyloid beta. In particular, it connects with amyloid beta oligomers (proteins that bind together to form a polymer), which are the protein's most toxic configuration. Without TREM2, microglia were much less successful at binding to, and clearing out, amyloid beta. Further investigation showed that removing TREM2 downregulated microglial potassium ion channels, impairing the electrical currents associated with the activation of these immune cells. In addition, TREM2 turned on a number of mechanisms associated with the amyloid beta response in microglia.
In the second study researchers added TREM2 to a mouse model with aggressive Alzheimer's disease. They found that the added TREM2 signaling stopped disease progression and even restored cognitive function. As they learn more about how TREM2 modulates the amyloid signals that put microglia to work, the researchers have their work cut out for them. "It could be beneficial in early stages to activate microglia to eat up amyloid beta, but if you over-activate them, they may release an overabundance of cytokines (causing extensive inflammation) damaging healthy synaptic junctions as a side-effect from overactivation." Still, the ability to use the brain's existing immune mechanisms to clear amyloid offers intriguing possibilities.