Evidence in Rats Suggests We Might Need to Rethink One of Alzheimer’s Main Culprits


Research into treatments for Alzheimer’s disease has hit dead end after dead end in recent years, suggesting we might need to rethink some of our most basic assumptions on this common form of dementia. 

 

Most focus has been on a build-up of proteins as if it’s directly responsible for the gradual loss of brain function. A new study on rats provides detail on how these proteins mess with cholesterol in the membranes of synapses, pointing to the real culprit of this insidious disease.

An investigation conducted by a team of researchers from Vanderbilt University in Tennessee and the Brain Institute at Florida Atlantic University has tracked the movements and changes in molecules of amyloid precursor protein (APP).

Until now, this protein has lived a rather shadowy existence, known more for its ties with dementia than its role in a healthy human nervous system.

It’s understood that the protein is snipped into smaller fragments, including a soluble version of APP, and a ‘beta’ form.

Exactly what each of these molecules does after they’ve broken free isn’t clear, but they potentially play a part in the adaptability of neurons or help manage other complex cellular processes.

For more than a century, researchers have associated aggregates of amyloid beta proteins inside nerve cells with an increasing loss of cognitive function.

 

In spite of intense medical research, we’re little closer to knowing whether these clumps cause disease, or if they just happen to be the benign product of a deeper pathological process.

Mutations in the APP gene are linked to rare cases of inherited forms of Alzheimer’s, after all. But scores of attempts to design Alzheimer’s treatments based on APP plaques as the primary culprit have fallen well short of expectations.

The message is slowly becoming clear – we’ve missed the forest for the clumps of diseased-looking trees.

To learn more about APP’s precise role in the functions of a typical rat brain cell, the research team labelled them with the chemical equivalent of tracking devices – pH sensitive fluorescent tags to measure their distribution and breakdown with unprecedented accuracy.

Letting the tagged APP molecules loose on samples of living rat tissue, the team watched them go about their business as the cells were gently stimulated.

For the most part, there were few surprises, with no clear sign of a relationship in APP locations and activity at the synapse.

 

What they did notice was a curious interaction between the proteins and the cholesterol molecules dotting the membranes at the nerve’s junctions.

The meeting of APP and cholesterol is no great shock on its own. Last year, University of Cambridge researchers showed how amyloid proteins tended to clump more near membranes rich in the substance. Their conclusion painted a scene of cholesterol encouraging the whole aggregation process thought to be behind Alzheimer’s.

It’s now starting to look a little backwards. 

While your dietician might give you a hard time on cholesterol in your diet, the fatty substance is an essential component of nerve cell membranes. A growing body of evidence is pointing to complex metabolic activity in our brain cells involving membrane lipids and a slew of proteinsincluding certain receptors.

Once the team forced the APP and cholesterol to part ways, they found the distribution of cholesterol was all messed up, connecting the dots between misbehaving proteins and vital lipid activity in the synapses of nerve cells.

“Our study is intriguing because we noticed a peculiar association between amyloid precursor protein and cholesterol that resides in the cell membrane of synapses, which are points of contact among neurons and the biological basis for learning and memory,” says Florida Atlantic University biomedical scientist Qi Zhang.

 

“Amyloid precursor protein may just be one of the many accomplices partially contributing to cholesterol deficiency.”

It’s still too early to tell if targeting cholesterol instead of rogue proteins would produce better results. Meanwhile, there’s no evidence suggesting we might be able to manage Alzheimer’s through tempering the cholesterol in our diet.

No doubt there will be more research on this intriguing relationship.

For the 47 million or so people living with the condition around the world, the finding is bittersweet.

Any prospective drugs looking to treat amyloid plaques might simply be bound to fail. But with so many studies pointing at cholesterol as the mastermind behind the disease, we might soon find ourselves on the right path again.

This research was published in Neurobiology of Disease.

 



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