While its exact causes are unknown, Alzheimer’s disease is commonly associated with clumps of toxic amyloid plaques in the brain, and researchers are continuing to understand the different components that help them take shape. Scientists at the University of Illinois at Urbana-Champaign have developed a new compound that attacks a number of the key players in the formation of amyloid plaques, significantly decreasing the level of plaques and reducing inflammation in the brain.
The presence of amyloid plaque buildup is considered a hallmark of Alzheimer’s, but it is thought that damage begins to occur in the brain long before these clumps appear. A great deal of research into the disease seeks to attack the building blocks of amyloid plaques. This includes protein fragments called beta-amyloid peptides, which may pose an even greater threat than the plaques themselves.
“Studies have found strong evidence that these soluble peptides are the most neurotoxic species and are causing memory loss and neuron cell death,” says Liviu Mirica, who led the new research. “Plaque formation might be an attempt by the brain to neutralize the threat.”
Along with beta-amyloid peptides, recent research has begun to illuminate the role metal ions might play in driving Alzheimer’s progression. Post-mortem studies have uncovered elevated levels of copper, iron, and zinc in the brains of sufferers, which are thought to interact with and stabilize the beta-amyloid peptides, as well as increasing oxidative stress and brain inflammation.
Yet another suspect in the onset of Alzheimer’s is a protein called p-tau, which studies have shown tends to gather around amyloid plaques and contribute to brain inflammation. These clumps of p-tau are thought to help create “neurofibrillary tangles” within neurons, which prevent proper function of cells and cause them to die.
“It’s possible that the amyloid plaques somehow trigger the aggregation of the p-tau proteins in the extracellular environment,” says Mirica. “And this process then spurs the spread and formation of p-tau inside the neurons, where it starts to clump together.”
Mirica and his team have been working on a multi-functional chemical agent that can attack these various components of Alzheimer’s, and have found success in a compound called L1.
“To address these different pathological aspects of Alzheimer’s disease, we developed a compound known as L1 that interacts with different regions of the beta-amyloid peptide, as well as with metal ions,” Mirica says. “When tested in mice genetically predisposed to develop Alzheimer’s-like pathologies, our compound could cross the blood-brain barrier, reduce neuroinflammation and decrease the levels of amyloid plaques and of p-tau aggregates associated with these plaques.”
The scientists note that a compound with this kind of effectiveness against this variety of factors related to the disease is unusual and imagine L1 could become a leading candidate in the pursuit of advanced treatments for Alzheimer’s disease.
The research was published in the journal ACS Chemical Neuroscience.
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