Research on treatments for Alzheimer's has reached a dead end in recent years, suggesting that we need to rethink some of our most basic assumptions about this common form of dementia.
The main focus was on building proteins as if they were directly responsible for the gradual loss of brain function. A recent study in rats describes in detail how these proteins become confused with cholesterol in the membranes of the synapses, indicating the real culprit of this insidious disease.
A study conducted by a team of researchers from Vanderbilt University in Tennessee and the Brain Institute of Florida Atlantic University has tracked the movements and changes in molecules of amyloid precursor protein (APP).
So far, this protein has lived a rather shadowy existence, known for its association with dementia as for its role in a healthy human nervous system.
It is known that the protein is broken down into smaller fragments, including a soluble version of APP and a beta form.
What exactly these molecules do after they have resolved is not clear, but they may play a role in the adaptability of neurons or help control other complex cellular processes.
For more than a century researchers have linked aggregates of amyloid beta proteins in nerve cells to an increasing loss of cognitive function.
Despite intensive medical research, we are hardly aware of whether these clots cause disease or whether they happen to be the benign product of a deeper pathological process.
After all, mutations in the APP gene are associated with rare cases of inherited forms of Alzheimer's disease. However, numerous attempts to make Alzheimer's treatments based on APP plaques as the main culprit far underperformed.
The message is getting clear – we have overlooked the forest because of the clumps of sick trees.
To learn more about the exact role of APP in the functions of a typical rat brain cell, the research team has provided them with the chemical equivalent of tracking devices – pH-sensitive fluorescent labels – to measure their distribution and breakdown with unprecedented accuracy.
The team released the labeled APP molecules from samples of living rat tissue and observed how they did their business while gently stimulating the cells.
In most cases, there were few surprises, and there were no clear signs of a relationship between APP locations and Synapse activities.
What they noticed was a peculiar interaction between the proteins and the cholesterol molecules that puncture the membranes at the junctions of the nerves.
The meeting of APP and cholesterol is not a big shock in itself. Last year, University of Cambridge researchers showed how amyloid proteins tended to clump near substance-rich membranes. Their conclusion drew a scene of cholesterol, which favors the entire aggregation process behind Alzheimer's.
Now it starts to look a little backwards.
While your nutritionist may find it difficult to cholesterol your diet, the fat is an integral part of nerve cell membranes. An increasing body of evidence points to complex metabolic activities in our brain cells that include membrane lipids and a number of proteins including certain receptors.
After forcing the APP and cholesterol to separate, the team found that the distribution of cholesterol was completely confused, linking the dots between malfunctioning proteins and vital lipid activity in nerve cell synapses.
"Our study is intriguing because we have found a special relationship between amyloid precursor protein and cholesterol, which resides in the cell membrane of synapses, which are points of contact between neurons and the biological basis for learning and memory," says biomedical scientist Qi Florida Atlantic University Zhang.
"Amyloid precursor protein can only be one of the many accomplices that contribute in part to cholesterol deficiency."
It is too early to say if targeting cholesterol instead of harmful proteins would give better results. In the meantime, there is no evidence that we could possibly manage Alzheimer's by controlling the temperature of cholesterol in our diet.
No doubt there will be more research on this fascinating relationship.
For the approximately 47 million people living with the disease around the world, the findings are bittersweet.
Any potential drug designed to treat amyloid plaques may fail. But with so many studies pointing to cholesterol as a thought leader of the disease, we could soon be back on track.
This research was published in Neurobiology of the disease,