One of the pathological hallmarks of Alzheimer’s disease is the accumulation of the protein, amyloid beta, in neurons, leading to the formation of plaques that impair brain function. Exactly how amyloid beta enters and becomes toxic to neuron, or nerve, cells, however, is a matter of debate — with a new study suggesting that that the protein leads to toxicity when it changes its structure in order to enter the neurons.
The study “Amyloid-β(1–42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity” was published in the journal Biological Chemistry.
Researchers found evidence that amyloid beta binds to the cell membrane, a membrane that delimits each neuron and separates its content from the surrounding environment, then undergoes a structural change, stacking its peptides onto each other. When these amyloid beta aggregates are formed, the whole structure is taken up by the neuron.
“Somewhere on this aggregation pathway, this type of structural element is formed for the amyloid beta to get into the cell,” Jan Bieschke, PhD, the study’s lead author, said in a news release. “There is a two-step process: amyloid beta can bind to the membrane and form aggregates while on the surface of the cell, then it gets taken up into the cell.”
The team also observed that, once inside neurons, amyloid beta aggregates interfere with the activity of the cells’ mitochondria, where energy is produced, causing an eventually fatal decrease in the nerve cells’ ability to generate essential energy. This observation may explain why patients in more advanced stages of Alzheimer’s show evidence of neuronal death in their brains.
According to Bieschke, the next step will be to investigate exactly how amyloid beta aggregates cause mitochondrial dysfunction, and whether the interaction with these structures occurs in ways similar to what was observed in the cell membrane. This information may help determine whether it is possible to manipulate the formation of the aggregates to avoid their accumulation in neurons, and a possible future therapeutic target in people with Alzheimer’s disease.
“This experimental evidence may improve our understanding of AD [Alzheimer’s] pathology and may inform more focused therapeutic approaches targeting membrane binding and self-assembly of the Aβ [amyloid beta] peptide,” the researchers wrote.
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