The most common neurodegenerative illness with motor, cognitive, and behavioral problems is Huntington’s disease, which is caused by a single gene.
Currently, there are no treatments that can stop or reverse the disorder, but new research from Boston Children’s Hospital suggests that there might be a method to protect the brain and delay or lessen cognitive decline.
Researchers from the Beth Stevens group have found that the immune system’s complement proteins and microglia play a role in the loss of certain synapses that connect the brain’s cortex and striatum. The research, which was recently published in Nature Medicine, might throw some light on other neurodegenerative diseases including Alzheimer’s.
The Stevens team was among the first to demonstrate in 2012 that during typical brain development, microglia engulf and prune synapses, fine-tuning the connections in the brain. Complement proteins tag synapses intended for removal, according to research from the lab.
According to Stevens and her team, this pruning mechanism is inappropriately triggered in conditions that cause synapse loss, including as Alzheimer’s disease, schizophrenia, and Huntington’s disease. Given that there is only one gene linked to the disease and that Huntington’s has a very well-defined pathology with early stages of the disease affecting particular brain regions and even specific synaptic connections between neurons, the disease presented an ideal opportunity to test their hypothesis.
Stevens and colleagues demonstrated that complement proteins and microglia are activated very early in the illness—before cognitive and motor symptoms appear—and that they target a specific vulnerable brain circuit in the pathway bridging the cortex and striatum. They did this using an animal model and postmortem brain samples from patients with Huntington’s disease.
It is known that corticostriatal circuits are involved in movement and learning which behaviors result in rewards. In particular, the striatum’s synapses were shown to have higher quantities of complement proteins, according to the researchers. Inputs from neurons in different brain regions that connect to the same cells were, however, comparatively unaffected.
The team avoided synapse loss by genetically eliminating the complement receptor CR3 on microglia or blocking the complement protein C1q in their animal model. They also avoided cognitive flaws related to visual learning, cognitive flexibility, and visual discrimination.
The study’s lead author, Dan Wilton, PhD, draws attention to an intriguing finding about Huntington’s disease: cognitive abnormalities typically appear before motor deficits, a pattern that is replicated in human instances. It becomes clear when the investigation goes into the specifics of this crippling ailment that the Huntington’s Disease model being examined also has modest motor problems. However, using complement blocking techniques, the research team, headed by Wilton, has identified viable possibilities for resolution.
Wilton and his colleagues offer information on a process that is distinguished by specificity and selective vulnerability by dissecting the complexity of Huntington’s disease. Their investigation includes the early stages of the illness, offering insightful information on what happens in these key first stages. Huntington’s disease is more nuancedly understood when cognitive difficulties, motor impairments, and the effectiveness of complement blocking techniques are combined, opening up possible management and intervention options.
In a ground-breaking discovery, the study reveals a biomarker that could revolutionize the diagnosis of Huntington’s disease. The study focuses on increased innate immune molecule concentrations in patients with Huntington’s disease’s cerebrospinal fluid. Surprisingly, these elevated levels coincide with a known predictor of pathological severity and disease initiation, appearing prior to the onset of motor symptoms. Dr. Stevens, a renowned employee of Boston Children’s Hospital’s FM Kirby Neurobiology Center and a member of the Broad Institute and Howard Hughes Medical Institute, exudes intense excitement. The possibility of using neuroimmune biomarkers to recognize people with the disease in its early stages opens doors for focused intervention and prioritized therapy, constituting an important step forward in the search for efficient management techniques.
Dr. Stevens explores the complexities of brain health and emphasizes the opportunity for innovation provided by clinical sample analysis, such as cerebrospinal fluid (CSF) analysis and biomarker measurement. This strategy might offer insightful views into how the brain functions, opening a window into the complexity of neurodegenerative diseases.
Dr. Stevens sees consequences that go beyond Huntington’s disease. The possibility that related mechanisms and biomarkers may be involved in other neurodegenerative diseases, such as Alzheimer’s and frontotemporal dementia, is being actively investigated by her lab. This multifaceted investigation highlights how thorough their research efforts were.
To understand the intricate mechanisms by which the huntingtin mutation activates complement, Dr. Stevens and her group are now doing research. It is necessary for cortical and striatal neurons to express the mutant huntingtin in a certain manner in order to start a process that leads to synaptic loss. The team, however, is adamant about solving the mystery of the corticostriatal inputs’ selective targeting.