Alzheimer’s has previously been understood to be caused by a build up of protein plaques in the brain. However, new research has revealed that alternative metabolic pathways in the brain may be more integral to the formation of the disease.

The plaques are formed by proteins known as beta-amyloid and tau. As Alzheimer’s progresses the plaques aggregate between the brain neurons and negatively impact the brain function. However, many therapies and drugs that have tried to prevent plaque build up have failed in clinical trials.

Previous research has indicated that lysosome storage is also predominant in the brains of Alzheimer’s patients. Lysosomes are cell organelles that break down proteins with impaired functionality back into their amino acid building blocks. The amino acids are then used to rebuild new proteins. However, if the lysosome cannot digest the protein then it continues to store it. The cell recognises the lysosome as faulty, stores it inside the cell and makes a new lysosome. If the proteins continue to not be digested lysosomes continue to be stored inside the cell and build up.

New research suggests that the proteins in Alzheimer’s plaques can undergo chemical changes that make them indigestible by lysosomes. The amino acids that make up the protein optically isomerize, which means they ‘flip’ their conformation. When the enzymes inside the lysosome attempt to digest the protein, they cannot attach themselves to the protein as its conformation is different. It is equivalent to trying to force a left-handed glove onto your right hand.

The researchers state that the likelihood of the protein conformation changing increases with time, which could explain why Alzheimer’s is usually only observed in older people.

This research has the potential to revolutionise new treatments for Alzheimer’s. These would work by promoting earlier protein recycling, in a process known as autophagy, before they have a chance to change conformation and become indigestible by lysosomes. 

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