Researchers Push for Therapeutic Targets to Prevent Synapse Loss in Huntington’s, Alzheimer’s Diseases

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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Therapeutic targets to prevent synapse loss in Huntington’s, Alzheimer's

Scientists at Boston Children’s Hospital have revealed the cellular and biological mechanisms involved in synapse loss in Alzheimer’s disease. By blocking certain agents involved in this process, scientists could halt synaptic loss, a discovery with therapeutic potential not only for Alzheimer’s, but also other diseases with loss of neuronal connections, including Huntington’s disease. The research paper, “Complement and microglia mediate early synapse loss in Alzheimer mouse models,” was published in Science.

Synapse loss is strongly correlated with the cognitive decline observed in Alzheimer’s disease, Huntington’s disease, frontotemporal dementia, and schizophrenia, among others. Currently used FDA-approved drugs for Alzheimer’s aim to boost cognition on a temporary basis, but do not address the events that lead to its loss. Previous research has shown that microglia — immune cells in the brain — and complement (a complex system of several proteins that act in concert to help eliminate infectious micro-organisms) are both involved as secondary events to plaque-related neuroinflammation.

However, microglia and complement are involved much earlier in the disease process and could be targeted to prevent synaptic loss and preserve functional synapses.

To understand how synapse loss begins, the team, led by Beth Stevens and Soyon Hong, used Alzheimer’s mouse models to study the events that lead to this loss, observing that microglia and complement mediate synaptic loss early in Alzheimer’s pathogenesis.

Researchers also found that the protein C1q, the initiating molecule of the complement cascade, is increased and associated with synapses before amyloid plaque deposition, one of Alzheimer’s hallmarks. Its activation tags synapses for elimination and is associated with synapse loss. Microglia then come into play and are responsible for synapses’ destruction.

By blocking either C1q, C3 (a protein downstream of C1q) or the C3 receptor on microglia, researchers found they could halt synaptic loss, indicating that both microglia and complement play important roles in this event and may be targeted as a therapeutic strategy to prevent synaptic loss.

ANX-005, a human form of the antibody used by the researchers to block C1q, is currently in early therapeutic development by Annexon Biosciences. Researchers believe it holds clinical potential for prevention of synaptic loss in several neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” Hong said in a news release. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”