School of Chemical Sciences

DCU Study Reveals How Brain Cell Receptors Influence Alzheimer's Protein Clumping

13/10/2025

Researchers have uncovered crucial new details about how amyloid beta proteins—the toxic clumps that characterize Alzheimer's disease—assemble at brain cell membranes, and discovered that two common antidepressants can break these aggregates apart.

The study, which used sophisticated microscopy and electrical measurement techniques on laboratory-created model membranes, reveals that different receptor molecules on neuron surfaces dramatically influence whether amyloid beta peptides bind and cluster together.

Membrane Receptors Matter

The team found that negatively charged receptors called PIP2 and phosphatidylserine (DOPS) strongly promote amyloid beta binding and aggregation, even causing pores to form in membranes. Among gangliosides—sugar-containing lipids abundant in brain tissue—GM1 and GM3 receptors facilitated the formation of distinct circular protein aggregates, while GD1a and mixed gangliosides largely prevented aggregation.

Using real-time electrical impedance measurements, the researchers could detect the onset of peptide aggregation at negatively charged membranes within 4-8 hours. Advanced imaging confirmed these findings, showing extensive protein association, membrane reorganization, and pore formation.

Repurposed Drugs Show Promise

Perhaps most significantly for potential therapy, the study demonstrated that two FDA-approved antidepressants—imipramine and fluoxetine—working together can disassemble membrane-bound amyloid beta aggregates within one to two hours without damaging the membrane itself.

Both drugs are selective serotonin reuptake inhibitors (SSRIs) known to reduce overall amyloid beta levels in brain fluid by 25%, and fluoxetine has been shown to reduce amyloid-induced toxicity at therapeutic concentrations. In humans, cumulative antidepressant use has correlated with less plaque buildup in brain imaging studies.

The researchers successfully removed aggregates from membranes containing GM1, GM3, DOPS, and PIP2 receptors using this drug combination. However, the drugs did not affect mature amyloid fibrils—the later-stage structures—suggesting they may be most useful for early intervention.

Clinical Implications

The advantage of drug repurposing is significant cost reduction and faster progression to clinical application, since these medications already have established safety profiles. Both drugs can cross the blood-brain barrier, making them viable candidates for treating brain diseases.