L1 compound identified as potential treatment for Alzheimer’s disease

When tested in brain cells and in a mouse model of Alzheimer’s disease, a newly identified compound significantly reduced the number of amyloid plaques in the brain, lessened brain inflammation and diminished other molecular markers of the condition.

Amyloid plaques are a hallmark of Alzheimer’s disease in the brain, as is the accumulation of a protein known as p-tau, said Professor Liviu Mirica, at the University of Illinois at Urbana-Champaign, US, who led the research. Recent studies show that aggregates of p-tau collect around amyloid plaques, increasing the neuroinflammation that is associated with Alzheimer’s. 

“It’s possible that the amyloid plaques somehow trigger the aggregation of the p-tau proteins in the extracellular environment,” Mirica said. “And this process then spurs the spread and formation of p-tau inside the neurons, where it starts to clump together.”

This clumping leads to the formation of ‘neurofibrillary tangles’ in the neurons that disrupt cell function and ultimately lead to cell death. Many studies have focused on dissolving or disrupting the formation of the amyloid plaques, which are composed of a protein fragment called the beta-amyloid peptide.

Previous research has found that soluble beta-amyloid fragments are more dangerous to brain health even before they aggregate into plaques.

“Studies have found strong evidence that these soluble peptides are the most neurotoxic species and are causing memory loss and neuron cell death,” Mirica said. Therefore, plaque formation might be an attempt by the brain to neutralise the threat.

Metal ions such as copper and iron also play a role in Alzheimer’s pathology. These metals form associations with the beta-amyloid peptide, stabilising the more dangerous, soluble beta-amyloid species. Metal ions also contribute to the damaging oxidative stress and brain inflammation seen in Alzheimer’s.

When tested in a mouse model of Alzheimer’s disease, a new compound, L1, reduced neuroinflammation, amyloid plaques and other molecular markers of the disease [credit: Hong-Jun Cho].

“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 said. “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 researchers say the findings suggest that drugs that interact with different regions of amyloid-beta protein fragments and other Alzheimer’s-associated peptides and metal ions could improve outcomes for people with Alzheimer’s disease. 

The findings were published in the journal ACS Chemical Neuroscience.