LA JOLLA, Calif.—Sanford Burnham Prebys Medical Research Institute (SBP) researchers have published two new studies in Neuron that 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 (AD), suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders.
“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,” says Dr. Huaxi Xu, professor and director of the Neuroscience Initiative, Jeanne & Gary Herberger Leadership Chair in Neuroscience, co-editor-in-chief of Molecular Neurodegeneration and senior author of the study. “The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer’s disease symptoms.”
“TREM2 offers a potential new strategy,” Xu notes. “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.”
As Xu tells DDNews, “TREM2 binds Abeta (amyloid beta) oligomers with a very high affinity, typically in the nM range. This may be protective, as Abeta/TREM2 interactions result in TREM2-mediated Abeta internalization and turnover. This will facilitate Abeta clearance by microglia, and limit the availability of free Abeta in the extracellular environment; this will reduce the Abeta load that contributes to neurotoxicity.
“Further, Abeta-TREM2 binding may trigger TREM2 downstream signaling events to activate microglia leading to increased cytokine releases enhancing immune-responses and phagocytosis towards Abeta plaques and dystrophic neurites.”
Xu led the first study, “TREM2 is a receptor for ß-amyloid which mediates microglial function,” which showed that TREM2 binds quite specifically to amyloid beta. In particular, it connects with amyloid beta oligomers, 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.
“As our results indicate a role for TREM2 in turning over Abeta, strategies that upregulate TREM2 function will likely reduce the amount of Abeta and Abeta plaques in the brain, especially at the early stage of disease. However, strategies targeting Abeta have not yet been successful; TREM2 enhancement strategies may need a combinatorial therapeutic which also targets other pathogenic agents such as tau,” notes Xu. “Our work with William Yang’s group in UCLA gives strong indication that increasing TREM2 dosage can reduce Abeta plaque load and improve cognition in AD mouse models.”
“TREM2 appears to be essential for microglial activation; this may be helpful with short-term Abeta exposure, where microglia would be able to sense, take up and clear Abeta in the brain,” he continues. “Deletion of the TREM2 gene blunts the activation response in microglia, which may impair mechanisms in the brain in place to sense and reduce the Abeta load.”
The second study, “TREM2 Gene Dosage Increase Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models,” was a collaboration led by Dr. X. William Yang, a professor in Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry & Biobehavioral Sciences at David Geffen School of Medicine at UCLA. This effort added TREM2 to a mouse model with aggressive Alzheimer’s disease. They found that the added TREM2 signaling stopped disease progression and restored cognitive function.
“Using contextual fear memory tests, AD models show a significant reduction in their memory capacity. With expression of additional TREM2, the cognitive behavior phenotype was almost normalized to that seen in wildtype mice. No difference in behavior is seen between wildtype mice alone, and wildtype mice overexpressing TREM2. What is also striking is that additional TREM2 expression can change the morphology of Abeta plaques from a diffuse pathology to a compact form. The effects of enhancing TREM2 expression are therefore quite remarkable,” Xu says.
“Cognitive function was measured in mouse models using a ‘contextual fear’ paradigm. In these tests, the mice are placed in a cage, and given an electrical foot shock, causing them to freeze. After repeated placement in this cage (consolidation of this memory stimulus, which is the electrical shock), the mouse will have memory of the shock response within the cage and freeze automatically without the electrical shock. If animals do not freeze (showing signs of movement), this indicates that their memory of this shock stimulus is impaired,” he adds. “When AD mice are placed in the contextual fear environment, they have an impaired memory of this cage and do not show freezing; however, AD mice overexpressing TREM2 showed a normal freezing phenotype comparable to wildtype mice, indicating that TREM2 overexpression largely restored memory function in an AD background.”
“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,” says Xu. “To our knowledge this provides convincing evidence that minimizing amyloid beta levels alleviates Alzheimer’s disease symptoms.
“A majority of the therapies that currently exist focus on limiting Abeta generation. This may not be ideal, as machinery that normally processes the Abeta precursor protein (APP) to Abeta also has other neuronal functions. What is exciting about this study is that we can enhance an endogenous mechanism set in place to sense Abeta to promote removal of Abeta. Whether or not this may be effective, or if this might produce other undesired effects will have to be tested in future studies.”
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 amyloid beta, but if you over-activate them, they may release an overabundance of cytokines, damaging healthy synaptic junctions as a side effect from overactivation. Going after microglia, rather than amyloid beta generation, may be a new research avenue for Alzheimer’s disease,” concludes Xu. “We could use brain immune cells to solve what’s becoming a public health crisis.”
