Nasal Alzheimer’s drug effective regardless of brain plaque levels
Researchers have found that an intranasal immunotherapy drug, currently being tested as a treatment for multiple sclerosis, reduced brain inflammation and improved cognition in mice with Alzheimer’s disease, independent of the amount of beta-amyloid plaques present. They say the treatment could benefit people in the later stages of the disease.
Most existing Alzheimer’s treatments focus on the buildup of the beta-amyloid protein plaques common to the disease. Studies have suggested that these plaques trigger the activation of microglia, the brain’s primary immune cells, which leads to inflammation and, ultimately, neuronal dysfunction and death.
Researchers from Brigham and Women’s Hospital in the US tested an intranasal monoclonal antibody therapy, currently being tested as a treatment for multiple sclerosis (MS), to see whether it’s effective in reducing the neuroinflammation associated with Alzheimer’s disease.
Monoclonal antibodies (mAbs) are lab-made antibodies that bind to specific cells or proteins to enlist the help of the body’s immune system to fight disease. In the current study, mice were given anti-CD3 mAbs intranasally three times a week for five months. Anti-CD3 are fully human mAbs that act as immunosuppressants by, in part, inducing the development of regulatory T (Treg) cells, which have a key role in suppressing the immune response.
The researchers found that intranasal anti-CD3 increased the number of Tregs in the periphery, which then migrated to the brain to dampen microglial activation and reduce neuroinflammation. They also found that, after testing the mice’s spatial learning and long-term memory, anti-CD3 improved cognition in both males and females. In a short-term memory test, the drug improved memory in females but not males. When they examined the effect of intranasal anti-CD3 on beta-amyloid accumulation, they found no change.
Since they found that anti-CD3 improved cognition independent of beta-amyloid accumulation, the researchers investigated whether the drug also affected gene expression in the cortex and hippocampus of the brain. The hippocampus is a crucial region for learning and memory and one of the brain areas affected by Alzheimer’s disease. They found that gene expression was altered in the hippocampus, cortex, and microglia, and these alterations were sex-dependent, which could explain the differences seen in short-term memory between male and female mice.
While anti-amyloid treatments have been developed to treat early-stage Alzheimer’s, there are few treatments being developed for people in the later stages of the disease. That anti-CD3 decreased neuroinflammation independently of beta-amyloid could be of benefit when anti-amyloid therapies are no longer effective.
“We provide evidence that intranasal anti-CD3 therapy can dampen microglia activation and expand T cells in a murine model of Alzheimer’s,” said Howard Weiner, corresponding author of the study. “This represents a unique approach to treating later-stage Alzheimer’s that can be applied to other inflammatory disease conditions as well.”
The researchers plan to conduct further experiments in animal models, combining anti-CD3 with therapies designed to reduce beta-amyloid, before moving to human trials.
The study was published in the journal PNAS.