Summary: Researchers suggest that activating specific immune checkpoints in microglia could help restore the balance between neuroprotection and neurotoxicity in several neurodegenerative diseases.
Source: Mass General.
Researchers at Massachusetts General Hospital (MGH) propose that targeting immune checkpoints—molecules that regulate immune activity—in microglia may reduce the damaging inflammation that accompanies major neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In a review published in the October issue of Nature Neuroscience, the team explains how dysregulated microglial activity contributes to neurodegeneration and identifies potential routes to restore protective microglial functions.
“Microglia perform three core roles in the brain,” says Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and the Division of Infectious Diseases, and the senior author of the review. “They act as sentinels that monitor the brain environment, as nurturers that support neuronal health by clearing debris and dying cells, and as warriors that defend against infection and toxins. In healthy tissue, immune checkpoints restrain the warrior response. When those checkpoints fail, microglial activity can initiate or accelerate neurodegeneration.”
Although microglia have long been recognized as the brain’s innate immune cells, the MGH team is the first to clearly characterize these three functional states based on gene expression signatures. After outlining how microglia normally carry out surveillance, maintenance, and defense, the authors review how these processes become harmful in several neurodegenerative diseases:
- Alzheimer’s disease: Microglia cluster around amyloid-beta plaques, and mutations in several microglial genes increase disease risk. When microglia cannot keep pace with ongoing amyloid-beta accumulation, they release inflammatory mediators that undermine their nurturing role. Over time this shift creates a disease-associated microglial state that sustains harmful neuroinflammation.
- Parkinson’s disease: Activated microglia are abundant in the substantia nigra—the region most affected in Parkinson’s disease. PET imaging has revealed widespread microglial inflammation early in disease progression. Similar to Alzheimer’s, initially protective responses can become dysregulated and turn into persistent, harmful inflammation.
- Amyotrophic lateral sclerosis (ALS): Inflammatory microglia have been observed near injured motor neurons in patient brains. In mouse models carrying mutant SOD1—a gene linked to inherited ALS—microglia appear protective at disease onset but shift to a neurotoxic state at later stages.
The review also details comparable transitions from protective to damaging microglial behavior in multiple sclerosis, Huntington’s disease, frontotemporal dementia, chronic traumatic encephalopathy, and other conditions. Across disorders, the loss of regulatory control over microglial defense responses emerges as a common driver of neuronal injury.
The authors highlight three candidate immune checkpoints that regulate microglial behavior: Trem2, which influences all three microglial functions; Cx3cr1, which controls sentinel and nurturer activities; and the progranulin pathway, which also supports surveillance and maintenance functions. Evidence implicates dysregulation of Trem2 and progranulin in Alzheimer’s, ALS and other diseases, while Cx3cr1 has been shown to modify disease courses in animal models of Alzheimer’s, Parkinson’s and ALS.
Immune checkpoint therapies revolutionized cancer treatment by blocking inhibitory checkpoints so the immune system can attack tumors. In contrast, the therapeutic goal for neurodegenerative disease would be to activate selected microglial checkpoints to reduce uncontrolled neuroinflammation, thereby restoring microglia to a protective state. El Khoury and colleagues emphasize that better understanding microglial gene regulation and behavior across disease stages is essential to translate this concept into therapies.
“We must analyze microglial transcriptional signatures across different diseases and stages, determine how aging and disease progression alter those patterns, and link these molecular changes to cell behavior,” El Khoury explains. “Translating findings from animal models to human patients is challenging and will require reliable cellular models derived from patient samples, improved imaging and analytical technologies, and methods to incorporate microglia into three-dimensional organoids. Developing these tools is a crucial next step.” El Khoury is an associate professor of Medicine at Harvard Medical School.
Suzanne Hickman, PhD, of the MGH Center for Immunology and Inflammatory Diseases is the lead author of the Nature Neuroscience review. Co-authors include Saef Izzy, MD, Pritha Sen, MD, and Liza Morsett, all of the Center for Immunology and Inflammatory Diseases.
Funding: The review was supported in part by National Institutes of Health grant RF1 AG051506.
Source: Terri Ogan – Mass General
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image in the public domain.
Original Research: Abstract for “Microglia in neurodegeneration” by Suzanne Hickman, Saef Izzy, Pritha Sen, Liza Morsett & Joseph El Khoury in Nature Neuroscience. Published September 26, 2018.
doi: 10.1038/s41593-018-0242-x
MLA: Mass General. “Regulating Microglial Activity May Reduce Inflammation in Neurodegenerative Diseases.” NeuroscienceNews, 18 October 2018.
APA: Mass General (2018, October 18). Regulating Microglial Activity May Reduce Inflammation in Neurodegenerative Diseases. NeuroscienceNews. Retrieved October 18, 2018.
Chicago: Mass General. “Regulating Microglial Activity May Reduce Inflammation in Neurodegenerative Diseases.” (accessed October 18, 2018).
Abstract
Microglia in neurodegeneration
The neuroimmune system plays critical roles in development, normal brain function, aging, and response to injury. Microglia—the primary immune cells of the central nervous system—perform three essential roles: constant environmental sensing (sentinel), maintenance and support of neuronal function (housekeeping/nurturer), and defensive responses to threats (defense/warrior). Microglia rely on defined gene programs to carry out these tasks. In response to certain stimuli or during neuroinflammation, microglia can also damage or kill neurons. Neuronal injury in Alzheimer’s, Parkinson’s, Huntington’s, prion diseases, ALS, frontotemporal dementia, and chronic traumatic encephalopathy often follows disruption of sentinel or housekeeping functions and dysregulation of defensive responses that lead to neuroinflammation. Key pathways involved in these processes include sensing and housekeeping mechanisms—such as the Trem2, Cx3cr1, and progranulin pathways—which act as immune checkpoints to limit microglial inflammation, and scavenger receptor pathways that aid in clearing harmful stimuli. Peripheral factors, including systemic inflammation and the gut microbiome, can also influence progression. An imbalance among these microglial functions can initiate or worsen neurodegeneration; restoring that balance may offer a promising therapeutic strategy.