Researchers have identified differences in how the brains of people with Alzheimer’s process a key protein. The discovery could lead to new diagnostic tests and possibly even treatments.

Alzheimer’s disease, which involves a progressive loss of memory and thinking skills, is the most common form of dementia.

In 2014, around 5 million people in the United States were living with Alzheimer’s, but as the population ages, that number is predicted to almost triple, reaching 14 million people by 2060.

In the brain of a person with Alzheimer’s, there is a buildup of insoluble plaques made of a protein called beta-amyloid and fibrous tangles of another protein, called tau.

Beta-amyloid is a fragment of a much larger protein called the amyloid precursor protein (APP), which is present in many organs, especially in the brain. Enzymes can break down APP in two ways, either by creating a beta-amyloid fragment or another, apparently harmless fragment.

Scientists at the Instituto de Neurociencias de Alicante, in Spain, have now found evidence that the way APP is “labeled” with sugar molecules may determine whether it gets broken down into beta-amyloid or the harmless type of fragment.

Their findings have been published in the journal Alzheimer’s Research & Therapy.

Ultimate destination

The process of adding sugar molecules to proteins during their production is known as glycosylation. The location of these molecules in a protein helps determine how it is processed and its ultimate destination in the cell.

“We have discovered that the glycosylation of the amyloid precursor in the brain[s] of Alzheimer’s patients is altered,” explains senior author Javier Sáez-Valero, a principal investigator at the institute. “And, therefore, this protein is probably being processed in a different way. We believe that this different way of processing leads to more beta-amyloid and to the triggering of the pathology.”

The researchers suspect that how APP is glycosylated may influence where it ends up in the cell membrane. This, in turn, may determine whether or not enzymes break it down to create beta-amyloid.

Fragments of APP find their way into the cerebrospinal fluid that bathes the brain and spinal cord. The discovery that these fragments are glycosylated differently in people with Alzheimer’s suggests that they could be used as biomarkers of the disease.

In the long term, the discovery could even inspire the development of treatments that prevent the creation of beta-amyloid and hence the buildup of plaques.

Postmortem samples

The researchers compared the glycosylation of APP fragments in postmortem brain samples from people who had Alzheimer’s and from people who didn’t have the disease.

They found different patterns of APP glycosylation in the two types of sample.

When they performed chemical analyses in cell cultures that produce APP, they found evidence that different patterns of glycosylation of APP might be associated with different processing of this protein.

“There is an indication that [APP] is synthesized differently and therefore can be processed in a different way, giving rise to the toxic cascade that triggers Alzheimer’s disease,” concludes Sáez-Valero.

The next step, say the researchers, will be to compare the glycosylation of APP fragments in the cerebrospinal fluid of people with Alzheimer’s and healthy participants in a control group.

Past attempts to use APP fragments as biomarkers of the disease have yielded mixed results.

“However, in view of our new results, we propose to repeat the studies carried out to date, not only by looking at the different types of fragments of the beta-amyloid protein, but also at its glycosylation,” says Sáez-Valero.

He and the rest of the team are confident that glycosylation could be the key to an effective diagnostic test for Alzheimer’s.

“Right now, we have a new tool that can be used in the short term for biochemical diagnosis of Alzheimer’s patients in the laboratory,” he says.

Much more work remains to be done, however, to determine whether changes in the glycosylation of APP directly cause the buildup of beta-amyloid in the brain.

In many ways, the puzzle of how Alzheimer’s disease develops has yet to be solved. For example, a recent study reported by Medical News Today cast doubt on the idea that the accumulation of beta-amyloid causes the condition.

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