A group of Massachusetts General Hospital (MGH) investigators is proposing that targeting immune checkpoints—molecules that regulate the activity of the immune system—in immune cells called microglia could reduce the inflammatory aspects of important neurodegenerative diseases like Alzheimer‘s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).
In their review article published in the October issue of Nature Neuroscience, they discuss how uncontrolled activity of microglia contributes to neurodegeneration in these and other neurodegenerative conditions.
“Microglia have three essential functions: a ‘sentinel’ function that surveys and senses changes within the brain, a ‘nurturer’ function that promotes neuronal wellbeing through actions such as removing dying cells and debris, and a ‘warrior’ function that defends the brain against infections and toxins,” explains Joseph El Khoury, MD , of the MGH Center for Immunology and Inflammatory Diseases and the Division of Infectious Diseases, senior author of the report.
“In healthy brains, immune checkpoints in microglia keep the ‘warrior’ function in check.
Disruption of those checkpoints initiates or propagates neurodegeneration.”
While microglia have long been recognized as the innate immune cells of the brain, the MGH team is the first to delineate these three functions, based on patterns of gene expression within the cells.
After detailing how microglia carry out these functions, the authors review how the processes can go awry in several neurodegenerative disorders:
An inability of microglia to keep up with persistent production of amyloid-beta leads to the release of inflammatory factors that further compromise the cells’ ‘nurturer’ functions, eventually transforming them into a disease-associated form that induces persistent, damaging neuroinflammation;
In Parkinson’s disease, activated microglia are known to be abundant in the substantia nigra, the brain structure that is damaged in the disease.
PET studies have shown widespread inflammatory microglia early in the course of the disease, and evidence suggests that the same sort of ‘double-edged sword’ situation seen in Alzheimer’s disease—in which initially protective microglia escape regulation, leading to persistent damaging neuroinflammation—also occurs in Parkinson’s.
In ALS, inflammatory microglia have been found near injured neurons in the brain of patients.
In a mouse model carrying a mutant SOD1 gene—one of several genes that, when mutated, can cause inherited forms of ALS—microglia have been found to be protective at disease onset but neurotoxic at later stages.
The investigators also describe how initially protective microglia can escape regulation and become damaging in multiple sclerosis, Huntington’s disease, and several other neurodegenerative conditions.
Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person’s physical and mental abilities during their prime working years and has no cure. HD is known as the quintessential family disease because every child of a parent with HD has a 50/50 chance of carrying the faulty gene. Today, there are approximately 30,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.
Many describe the symptoms of HD as having ALS, Parkinson’s and Alzheimer’s – simultaneously.
Symptoms usually appear between the ages of 30 to 50, and worsen over a 10 to 25 year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Everyone has the gene that causes HD, but only those that inherit the expansion of the gene will develop HD and perhaps pass it on to each of their children. Every person who inherits the expanded HD gene will eventually develop the disease. Over time, HD affects the individual’s ability to reason, walk and speak.
Personality changes, mood swings & depression
Forgetfulness & impaired judgment
Unsteady gait & involuntary movements (chorea)
Slurred speech, difficulty in swallowing & significant weight loss
The team identifies three potential immune checkpoints in microglia—Trem2, which regulates all three functions; Cx3cr1, which regulates the sentinel and nurturer functions, and the progranulin pathway, which also regulates sentinel and nurturer functions.
Evidence points to dysregulation of both Trem2 and progranulin in Alzheimer’s disease, ALS and other disorders; and Cx3cr1 is known to alter the course of disease in animal models of Alzheimer’s disease, Parkinson’s disease, ALS and other disorders.
While immune checkpoint therapies for cancer—discovery of which recently received the Nobel Prize in Medicine—are designed to inhibit checkpoints that prevent the immune system from attacking tumor cells, in neurodegenerative disease the goal would be to activate checkpoints that could reduce and potentially eliminate out-of-control neuroinflammation, returning microglia to their healthy neuroprotective state.
Several rare mutations in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene are associated with increased risk for Alzheimer’s disease (AD), with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele (Guerreiro et al., 2013; Jonsson and Stefansson, 2013; Jonsson et al., 2013). TREM2 is an immunoreceptor expressed on myeloid cells, including immature dendritic cells, osteoclasts, macrophages, and microglia, and transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). In the brain, TREM2 is one of the most highly expressed receptors in microglia and has been found to modulate microglia-mediated phagocytic clearance of apoptotic neurons and inflammatory responses (Hickman and El Khoury, 2014). Individuals with genetic mutations inactivating TREM2 or DAP12 develop Nasu–Hakola disease with cystic-like lesions of the bone and brain demyelination, respectively, leading to fractures and presenile dementia (Paloneva et al., 2002; Klünemann et al., 2005), implying a critical role of TREM2 in maintaining the homeostasis of the CNS.
Microglia, which account for 5–10% of the total cell population in mammalian brains, play important roles in the brain innate immune system (Lawson et al., 1990; Block et al., 2007; Polazzi and Monti, 2010; Aguzzi et al., 2013; Malik et al., 2015). Microglia rapidly extend processes to the sites of injury, migrate to lesion sites, recognize pathogens, and ramify and mount immune responses, including the release of cytokines and phagocytosis of damaged debris (Ransohoff and Perry, 2009). In the brains of both AD patients and mouse models, microglia are found to be closely associated with amyloid plaques and exhibit an “activated” proinflammatory phenotype (Perlmutter et al., 1990; Frautschy et al., 1998; Lee and Landreth, 2010). Microglia maintain their numbers through self-repopulation and alter their appearance and numbers during AD pathogenesis (Ajami et al., 2007; Wes et al., 2016). TREM2 is specifically expressed in microglia in the healthy brain (Hickman et al., 2013), whereas TREM2 deficiency has been shown to reduce microgliosis in 5×FAD mice with amyloid plaques not fully enclosed by microglia (Wang et al., 2015; Wang et al., 2016; Yuan et al., 2016). Although it has been suggested that microglial TREM2 modulates immune responses and affects amyloid pathology in AD (Painter et al., 2015; Colonna and Wang, 2016; Ulrich and Holtzman, 2016), the molecular pathways underlying TREM2-regulated microglial survival remain unclear.
El Khoury and his colleagues are now working to improve understanding of how microglia contribute to neurodegeneration.
“Analyzing patterns of microglial gene transcription and regulation in several disease states, understanding how those patterns may be altered by aging and disease progression, and correlating those changes to microglial behavior is essential,” he says.
“Expanding studies from animal models to human patients remains a challenge that will require development of new, reliable cellular models based on patient samples and additional technologies for imaging and analysis.
And new techniques to incorporate microglia into three-dimensional organoids—miniature organs grown from living tissues—are a crucial next breakthrough that needs to be achieved.” El Khoury is an associate professor of Medicine at Harvard Medical School.
More information: Suzanne Hickman et al, Microglia in neurodegeneration, Nature Neuroscience(2018). DOI: 10.1038/s41593-018-0242-x
Journal reference: Nature Neuroscience search and more info website
Provided by: Massachusetts General Hospital