A drug candidate designed by researchers at the National Institute on Aging (NIA) protected mouse models of Alzheimer's disease from cognitive decline and reduced inflammation in their brains. The corresponding study was published in Alzheimer's and Dementia.
Drugs that target amyloid-beta plaques and tau protein build-ups are largely ineffective in mitigating cognitive impairment arising from Alzheimer's disease, even though these factors are considered biomarkers for the condition. Their lack of efficacy has prompted researchers to look into new drug targets.
One potential target is neuroinflammation caused by Tumor Necrosis Factor-alpha (TNF alpha), an inflammatory cytokine involved in cell death. However, researchers have had difficulty finding compounds that can lower TNF alpha that can cross the blood-brain barrier.
In the present study, researchers evaluated the efficacy of a new drug candidate that could potentially cross the blood-brain barrier: 3,6’-dithiopomalidomide (DP). To do so, they used a mouse model designed to produce up to five times the normal levels of beta-amyloid plaques to exemplify Alzheimer's disease.
Four months of treatment with DP significantly reduced brain inflammation in the mice and reduced synaptic loss and neurodegeneration. They further noted that the drug was well-tolerated overall and led to behavioral and cognitive improvements among mice when tested with laboratory tasks, in areas including spatial and working memory, as well as anxiety and motor function.
The researchers say that their results demonstrate that neuroinflammation, which occurs decades before symptoms of Alzheimer's may occur, should be considered as a target pathway for future drug development against the condition.
"Our study provides an avenue for future [Alzheimer's disease] clinical studies by using the immunomodulating imide drug class to mitigate neuroinflammation, and a framework to evaluate the sequence of amyloid-beta-initiated cascades in driving [Alzheimer's disease]," wrote the researchers.
"Additionally, it accounts for past amyloid-beta centric drug failures and the presence of high amyloid-beta load in healthy individuals who may not have neuroinflammation," they continued.