AEV103 Can Quell Brain Inflammation, Slow Cognitive Decline in Mice
AEV103 (3,6’-dithiopomalidomide), a potentially immunomodulating medicine, was able to quell brain inflammation and slow cognitive decline in a mouse model of Alzheimer’s disease, a study has found.
The medicine, developed originally at the National Institutes of Health (NIH) and now licensed to AevisBio, exerted its effects even in the absence of any change in the levels of amyloid-beta, the protein that clumps together to form the toxic deposits that cause the death of nerve cells (neurons) in Alzheimer’s.
These findings build on previous work about the importance of targeting inflammation of the nervous system (known as neuroinflammation) — and support what might one day become a new therapeutic strategy for Alzheimer’s and other neurological diseases.
“We are grateful to our scientific collaborators and investors for their support as we advance a new generation of immunomodulatory drugs that have the potential to be disease-modifying for neuroinflammation-driven neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases and traumatic brain injury,” Dong Seok Kim, PhD, founder and CEO of AevisBio, said in a press release.
The study, “Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis,” was published in Alzheimer’s & Dementia. The research was conducted by an international team including researchers from AevisBio and the NIH’s National Institute on Aging.
Neuroinflammation is triggered by amyloid-beta deposits in the brain and is thought to play a role in neurodegeneration. Addressing neuroinflammation can provide “multiple potential targets” for the development of novel Alzheimer’s therapies. However, whether the development of neuroinflammation actively drives disease progression is not yet completely understood.
“The objective of our study is to demonstrate the direct involvement of neuroinflammatory processes in the development of synaptic dysfunction and loss and consequent cognitive impairment,” the researchers wrote. Synapses are the junctions between two nerve cells that allow them to communicate. Synaptic function is thought to be gradually impaired throughout the course of Alzheimer’s.
In this study, the researchers used AEV103, a compound that binds to a protein called cereblon. This protein is involved in the degradation of other proteins, a normal process of protein turnover that occurs within cells in the body. Among other functions, protein degradation helps the cells get rid of harmful proteins, such as those that accumulate within nerve cells in Alzheimer’s.
AEV103 is thought to lower the levels of a pro-inflammatory protein known as tumor necrosis factor-alpha (TNF-alpha), which is mainly secreted by a type of brain immune cell called microglia.
The researchers grew neurons and microglia together in the presence of amyloid-beta. As a result, microglia were activated, meaning they were ready to make and release inflammatory molecules, such as TNF-alpha. Consequently, there was a reduction in the number of neurons that remained alive. However, when researchers added AEV103 to the pool of cells, microglial activation was reduced and more neurons remained alive. The neurons also grew more neurites, which are the long projections that usually relay nerve impulses.
Next, the researchers used a mouse model of Alzheimer’s that develops high levels of neuroinflammation resulting from a buildup of amyloid-beta, as well as cognitive impairment.
Animals were treated with AEV103 daily for four months, starting at the time amyloid-beta deposits were first observed in their brains. Treated mice did not lose weight compared to untreated mice, indicating that the treatment was well-tolerated.
When the researchers watched for changes in cognitive impairment, they found that treated mice showed better spatial working memory and less anxiety than untreated mice. Moreover, their brains showed less inflammation, including lower levels of TNF-alpha, and fewer dying neurons. Spatial working memory reflects the capacity to temporarily store and process spatial information.
Interestingly, these effects occurred even in the absence of any change in the levels of brain amyloid-beta deposits.
“We interpret this as amyloid-[beta]-induced neuroinflammation providing an essential link in the cascade leading to neurodegeneration and cognitive loss, and potentially accounting for failure of amyloid-[beta] centric treatments initiated after amyloid-[beta] neuroinflammation has been triggered,” the researchers wrote.
This means that neuroinflammation might be able to directly drive cognitive decline.
“The immunomodulatory activity of AEV103 elucidates the role of neuroinflammation in cognitive decline, building upon the amyloid hypothesis and providing a new therapeutic approach independent of amyloid beta clearance,” said Kim, who also is one of the study’s authors.
According to the press release, AevisBio has raised $10 million in funding to evaluate the safety of AEV103 and other candidates as potential treatments for neurodegenerative disorders.