Immune cells in the brain have a trigger, and when it is pulled, it prompts immune cells to degrade toxic β-amyloid (Aβ) proteins. This new finding, from Sanford Burnham Prebys Medical Research Institute (SBP), helps explain why a faulty trigger appears to raise the risk of Alzheimer’s disease. Increasing the genetic expression of the trigger—a way of pulling the trigger more often—could prevent or reduce the severity of Alzheimer’s disease and other neurodegenerative disorders.
The trigger is called triggering receptor expressed on myeloid cells 2 (TREM2). TREM2’s amyloid-binding mechanism and its potential use against Alzheimer’s were discussed in two papers that appeared March 7 in the journal Neuron.
“Our first paper identifies how Aβ binds to TREM2, which activates neural immune cells called microglia to degrade Aβ, possibly slowing Alzheimer's disease pathogenesis,” said Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative. “The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms.”
The first paper (“TREM2 Is a Receptor for β-Amyloid That Mediates Microglial Function”) describes how TREM2 directly binds to Aβ oligomers with nanomolar affinity, whereas Alzheimer’s disease–associated TREM2 mutations reduce Aβ binding. It also indicates that TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain.
“Aβ-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2,” wrote the article’s authors. “In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β.”
Essentially, TREM2 binds quite specifically to Aβ. In particular, TREM2 connects with Aβ oligomers, which are the protein’s most toxic configuration. Further investigation showed that removing TREM2 downregulated microglial K+ 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 Aβ response in microglia.
The second study (“Elevated TREM2 Gene Dosage Increase Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models”) added TREM2 to a mouse model with aggressive Alzheimer's disease. In this study, the SPD team found that the added TREM2 signaling stopped disease progression and even restored cognitive function.
“Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes,” the study indicated, adding that mice modified to express more TREM2 “showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation.
“Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models.”
Alzheimer's disease affects more than 47 million people worldwide, a number expected to grow as the population ages. One of the hallmarks of the 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 Aβ production to thwart Alzheimer's—but with minimal success.
“TREM2 offers a potential new strategy,” asserted Dr. Xu. “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 Aβ and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease.
“These studies are important because they show that in addition to rescuing the pathology associated with Alzheimer's disease, we are able to reduce the behavioral deficits with TREM2,” added Dr. Xu. “To our knowledge, this provides convincing evidence that minimizing Aβ levels alleviates Alzheimer's disease symptoms.” As they learn more about how TREM2 modulates the amyloid signals that put microglia to work, the Xu lab and other researchers have their work cut out for them.
“It could be beneficial in early stages to activate microglia to eat up Aβ,” explained Dr. Xu, “but if you overactivate 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. “Going after microglia, rather than Aβ generation, may be a new research avenue for Alzheimer's disease,” suggested Xu. “We could use brain immune cells to solve what's becoming a public health crisis.”