Blocking immune system proteins may help in Huntington’s: Study

Strategy found to protect brain connections in mouse model

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Blocking immune system proteins that are part of the body’s complement cascade — which helps the immune system to fight infection — was found to protect nerve cell connections between two brain regions known to be affected in Huntington’s disease in a mouse model of the rare disorder. It also helped to prevent cognitive deficits in the mice.

Overall, this strategy helped protect corticostriatal synapses, the nerve cell connections between the brain’s cortex and striatum that are involved in motor and cognitive function, including decision making.

Evidence from the Huntington’s mouse models and patients suggested that components of the complement system and microglia — the brain’s resident immune cells — mediate corticostriatal synapse loss. That loss has been previously implicated in Huntington’s-associated cognitive impairments.

“Our study outlines the mechanisms underlying selective elimination of corticostriatal synapses in Huntington’s disease and shows that these can be targeted to prevent synapse loss and halt the development of cognitive impairments. We believe this has potentially important implications for the development of therapeutics as well as the identification of biological markers of disease progression,” Beth Stevens, PhD, the study’s senior author, and Daniel Wilton, PhD, the study’s first author, said in an emailed statement to Huntington’s Disease News. Both Stevens and Wilton are in the department of neurology at Harvard Medical School’s Boston Children’s Hospital.

The study, “Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease,” was published in Nature Medicine.

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Synapses are the place of near contact between nerve cells where they release electrical and chemical signals to communicate with each other.

Previous research from Stevens’ lab showed that, during normal brain development, microglia engulf and eliminate unnecessary or inactive synapses. They do so to fine-tune brain function in a process called synaptic pruning. The immune complement cascade was shown to tag which synapses the microglia should clear away.

As such, Stevens and her team, including Wilton and other researchers at Boston Children’s, and colleagues from other institutions, believe that aberrant synaptic pruning later in life may contribute to neurodegenerative conditions like Huntington’s.

Indeed, there is evidence that corticostriatal synapses — those connecting nerve cells in two brain regions called the cortex and the striatum — are lost early on in Huntington’s, and that this is linked to cognitive declines.

The brain’s corticostriatal pathway is important for goal-directed behaviors, cognition, and movement. However, the mechanisms behind this corticostriatal synapse loss remain unclear.

It’s also not known if this loss occurs before onset of motor and cognitive symptoms, or why these specific connections are more vulnerable than others.

Now, the researchers showed that the complement cascade and microglia are involved in Huntington’s-associated corticostriatal synapse loss.

The scientists examined two Huntington’s mouse models, as well as brain samples both from deceased Huntington’s patients with varying degrees of neurodegeneration, and age-matched healthy people. They found a selective loss of corticostriatal synapses, while synapses in a brain region less affected by the disease were preserved.

Importantly, this synapse loss was detected early on in the disease, specifically in mice not yet showing motor or cognitive deficits, and in Huntington’s patients with pre-manifest disease. Patients with pre-manifest disease are those with disease-causing mutations who don’t yet have symptoms.

“Taken together, these results show that corticostriatal synapse loss is an early event in” Huntington’s disease development, the researchers wrote.

The complement component 1q, called C1q, which starts the complement signaling cascade, and complement component 3, known as C3 — a downstream protein that directly signals to microglia — were found to accumulate around corticostriatal synapses.

Microglia in the area also showed a shift toward a more phagocytic profile, meaning they were primed to actively engulf substances in their environment.

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Further experiments demonstrated that the complement- and microglia-mediated corticostriatal synapse loss was dependent on the production of mutant huntingtin (mHTT), the protein that toxically accumulates in Huntington’s, by both cortical and striatal nerve cells.

Strategies to block the detrimental effects of complement activation were found to protect corticostriatal synapses in the mouse model. This was observed with genetic deletion of CR3, the protein at the surface of microglia that recognizes C3, as well as with treatment with a C1q-targeted antibody.

While the CR3 deletion approach had no effect on the accumulation of C1q and C3 bound to corticostriatal synapses, it was able to also prevent cognitive impairments and subtle motor deficits.

“We showed what happens to synapses in the brain at the earliest stages of Huntington’s Disease, before the appearance of motor symptoms,” Stevens and Wilton said.

The C1q-targeted antibody used in the study was obtained from Annexon Biosciences, which is developing a similar one called ANX005 as a potential treatment for Huntington’s and other conditions.

The experimental antibody was tested in adults with early Huntington’s and those at risk for the disease as part of a Phase 2 clinical trial called ANX005-HD-01 (NCT04514367), which had promising results. Annexon has indicated that it plans to launch a Phase 3 trial in Huntington’s in 2024.

“Our findings validate a treatment in clinical trials for Huntington’s that blocks C1q with an antibody,” Stevens and Wilton said.

We showed what happens to synapses in the brain at the earliest stages of Huntington’s Disease, before the appearance of motor symptoms.

Additional experiments also indicated that complement proteins could make for good disease biomarkers.

Levels of C3 and iC3b were significantly elevated in the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord, of early-manifest Huntington’s patients relative to pre-manifest patients. Also, levels of these proteins correlated with measures of disease burden.

“We’re excited by the idea that we could identify neuroimmune biomarkers to stratify people at the earliest stage and prioritize some for treatment,” Stevens said in a press release.

“If you had clinical samples such as CSF, measuring these biomarkers could bring insight into what is happening in the brain,” she added.

In ongoing research, the scientists are looking to better understand how mHTT contributes to abnormal complement activation. As things stand, it is still not known why these specific corticostriatal synapses may be targeted. “That’s a major future direction for our group,” Stevens said in the release.

Beyond Huntington’s, the team is exploring whether similar mechanisms might be at play in other neurodegenerative diseases like Alzheimer’s disease.

Stevens serves on Annexon’s scientific advisory board and is a minor shareholder, while another of the study’s authors is a company employer.