Researchers from the University of California, Riverside, have offered new evidence suggesting dysfunction in the lysosome system, our body's cellular garbage disposal mechanism, could be the underlying cause of Alzheimer's disease. The hypothesis is not entirely novel but the research describes a newly discovered process to explain how lysosomal failure can lead to neurodegenerative disease.
"The dominant theory [of Alzheimer's disease] based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed," explains RyanJulian, lead on the UC Riverside team.
Over the last few years a number of alternative Alzheimer's hypotheses, previously inhabiting the fringes of mainstream science, have been more seriously reconsidered. From viral hypotheses examining herpes and gum disease, to suggestions high iron levels can trigger the disease, a variety of different ideas are currently being investigated.
The new study focuses on lysosomes, a tiny organelle present in many animal cells. Lysosomes serve several functions, but one of their primary roles is to break down and clear out obsolete or unnecessary molecules within a cell. Consequently, they are quite reasonably referred to as a cell's garbage disposal system.
When a lysosome has trouble breaking down a protein its host cell pauses that activity and generates a new, hopefully functional lysosome. The old dysfunctional lysosome is subsequently "stored" within the cell, but when this process continually repeats, a number of dysfunctional lysosomes can accumulate in a given cell. This scenario results in a lysosomal storage disease. These diseases are relatively rare, are primarily related to genetic mutations, and result in death within a few years of birth.
"The brains of people who have lysosomal storage disorder, another well-studied disease, and the brains of people who have Alzheimer's disease are similar in terms of lysosomal storage," says Julian. "But lysosomal storage disorder symptoms show up within a few weeks after birth and are often fatal within a couple of years. Alzheimer's disease occurs much later in life. The timeframes are, therefore, very different."
Prior research has found increased concentrations of dysfunctional lysosomes in those suffering from Alzheimer's disease. These lysosome concentrations occur in the presence of neurons that are being choked by toxic accumulations of amyloid and tau proteins. But exactly why these lysosomes are unable to break down and clear amyloid and tau proteins has been a mystery.
The new research suggests these toxic proteins associated with Alzheimer's disease have the ability to spontaneously change their molecular structures. These proteins can essentially flip into a mirror image, and the new study claims this makes them indigestible to lysosomes.
"Enzymes that ordinarily break down the protein are then notable to do so because they are unable to latch onto the protein," Julian explains. "It's like trying to fit a left-handed glove on your right hand. We show in our paper that this structural modification can happen in beta-amyloid and tau, proteins relevant to Alzheimer's disease. These proteins undergo this chemistry that is almost invisible, which may explain why researchers have not paid attention to it."
The overarching hypothesis presented here is that Alzheimer's disease is caused by this lysosome dysfunction, resulting in neuronal damage on two fronts. The amyloid and tau accumulations, unable to be effectively cleared by the lysosomes, inevitably cause permanent neuronal damage. But the accumulation of dysfunctional lysosomes also add to this neurodegeneration associated with Alzheimer's.
Prior research from scientists at Yale University has suggested that the build-up of failed lysosomes in the brain can enhance the accumulation of toxic proteins. That research hypothesized targeting the removal of these dysfunctional lysosomes to be a potential Alzheimer's treatment.
This new research from the UC Riverside team suggests an alternative treatment hypothesis – finding a way to stop the toxic proteins from changing their structure, which would allow the lysosomes to effectively clear them from the brain. This would halt the chain reaction that causes the neurodegeneration associated withAlzheimer's.
"It's been long known that these modifications happen in long-lived proteins, but no one has ever looked at whether these modifications could prevent the lysosomes from being able to breakdown the proteins," says Julian. "One way to prevent this would be to recycle the proteins so that they are not sitting around long enough to go through these chemical modifications. Currently, no drugs are available to stimulate this recycling – a process called autophagy – for Alzheimer's disease treatment."
Restoring the body's ability to clear toxic Alzheimer's-inducing proteins from the brain is certainly not a new therapeutic strategy, and neither is focusing on the lysosomal system to achieve this. The new research does, however, offer a compelling hypothesis as to why lysosomes struggle with clearing amyloid and tau, suggesting research directions for novel future therapeutic drugs.
The new study was published in the journal ACS Central Science.
Source: UC Riverside