An alternate theory for what causes Alzheimer's disease

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An alternate theory for what causes Alzheimer's disease

A UC Riverside study points to lysosomal storage observed in all brains afflicted with the disease; finding could open up new avenues for treatment and prevention

A new explanation on the cause of Alzheimer's disease
This new study focuses on lysosomes, a tiny organelle found in many animal cells. Lysosomes perform several functions, but one of their main roles is to remove unnecessary waste or molecules within a cell.

Alzheimer's disease (AD), the most common type of dementia, is an irreversible and progressive neurodegenerative disorder causing cognitive and functional impairment. It is characterized by formation of protein aggregates and progressive loss of neurons in the central nervous system (CNS). The symptoms of AD include short-term memory loss, confusion, irritability, aggression and mood swings, progressing to long-term memory deficit, withdrawal from social interactions and subsequently a loss in higher central functioning.

When a lysosome has difficulty breaking down a protein, its host cell pauses this activity and generates a new functional lysosome. The old dysfunctional lysosome is then "stored" in the cell, but when this process is continuously repeated, a number of dysfunctional lysosomes can accumulate in a given cell.

This scenario leads to a lysosomal storage disease. These diseases are relatively rare, and are mainly linked to genetic mutations that cause death a few years after birth.

"The brains of people with lysosomal storage disorder, another well-studied disease, and those of people with Alzheimer's disease are similar in terms of lysosomal storage," says Julian. "But the symptoms of lysosomal storage disorder appear after a few weeks after birth and are often fatal after a few years. Alzheimer's disease occurs much later in life. The deadlines are therefore very different. »

An increase in dysfunctional lysosomes in Alzheimer's disease
Previous research has shown an increase in dysfunctional lysosome concentrations in people with Alzheimer's disease. These lysosome concentrations occur in the presence of neurons suffocated by toxic accumulations of amyloid and tau proteins. But precisely why these lysosomes are unable to decompose and eliminate amyloid and tau proteins is a mystery.

New research suggests that these toxic proteins associated with Alzheimer's disease have the ability to spontaneously modify their molecular structures. These proteins can essentially fall into a mirror image, and the new study claims that this makes them non-digestible to lysosomes.

"The enzymes that usually break down proteins can't do that, because they can't include the protein," Julian explains. "It's like trying to fit a left-handed glove to your right hand. We show in our article that this structural change can occur in beta-amyloid and tau proteins, which are important in Alzheimer's disease. These proteins undergo this almost invisible chemistry, which may explain why researchers have not paid attention to them. "

This new research from the UC Riverside team suggests another hypothesis for treating Alzheimer's disease: finding a way to prevent toxic proteins from changing their structure, which would allow lysosomes to effectively remove them from the brain. This would stop the chain reaction that causes neurodegeneration associated with Alzheimer's disease.

"It has long been known that these changes occur in long-lived proteins, but no one has ever questioned whether these changes could prevent lysosomes from being able to break down these proteins," Julian said. "One way to avoid this would be to recycle these proteins so that they do not stay long enough to undergo these chemical changes. At present, no drugs are available to stimulate this recycling - a process called autophagy - for the treatment of Alzheimer's disease. "

A convincing hypothesis
Restoring the body's ability to remove toxic Alzheimer's disease-inducing proteins from the brain is certainly not a new therapeutic strategy, nor is the lysosomal system to do so. However, this new research offers a convincing hypothesis on why lysosomes fight against the elimination of amyloid and tau protein, suggesting avenues for research into new therapeutic drugs.