New Alzheimer's hypothesis suggests cellular garbage disposal system could be key to prevention
Researchersfrom the University of California, Riverside, have offered newevidence suggesting dysfunction in the lysosome system, our body'scellular garbage disposal mechanism, could be the underlying cause ofAlzheimer's disease. The hypothesis is not entirely novel but theresearch describes a newly discovered process to explain howlysosomal failure can lead to neurodegenerative disease.
"The dominant theory [of Alzheimer's disease] based on beta-amyloid buildup has beenaround for decades, and dozens of clinical trials based on thattheory 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, previouslyinhabiting the fringes of mainstream science, have been more seriouslyreconsidered. 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 inmany animal cells. Lysosomes serve several functions, but one of theirprimary roles is to break down and clear out obsolete or unnecessarymolecules 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 cellpauses that activity and generates a new, hopefully functionallysosome. The old dysfunctional lysosome is subsequently "stored"within the cell, but when this process continually repeats, anumber of dysfunctional lysosomes can accumulate in a given cell. Thisscenario results in a lysosomal storage disease. These diseases arerelatively rare, are primarily related to genetic mutations, and resultin 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 haveAlzheimer's disease are similar in terms of lysosomal storage,"says Julian. "But lysosomal storage disorder symptoms show upwithin a few weeks after birth and are often fatal within a couple ofyears. Alzheimer's disease occurs much later in life. The timeframes are, therefore, very different."
Prior research has found increased concentrations of dysfunctionallysosomes in those suffering from Alzheimer's disease. Theselysosome concentrations occur in the presence of neurons that arebeing choked by toxic accumulations of amyloid and tau proteins. Butexactly why these lysosomes are unable to break down and clearamyloid and tau proteins has been a mystery.
The new research suggests these toxic proteins associated withAlzheimer's disease have the ability to spontaneously change theirmolecular structures. These proteins can essentially flip into amirror image, and the new study claims this makes them indigestibleto 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 onyour right hand. We show in our paper that this structuralmodification can happen in beta-amyloid and tau, proteins relevant toAlzheimer's disease. These proteins undergo this chemistry that isalmost invisible, which may explain why researchers have not paidattention to it."
The overarching hypothesis presented here is that Alzheimer'sdisease is caused by this lysosome dysfunction, resulting in neuronaldamage on two fronts. The amyloid and tau accumulations, unable to beeffectively cleared by the lysosomes, inevitably cause permanentneuronal damage. But the accumulation of dysfunctional lysosomesalso add to this neurodegeneration associated with Alzheimer's.
Prior research from scientists at Yale University has suggestedthat the build-up of failed lysosomes in the brain can enhance theaccumulation of toxic proteins. That research hypothesized targetingthe removal of these dysfunctional lysosomes to be a potentialAlzheimer's treatment.
This new research from the UC Riverside team suggests an alternativetreatment hypothesis – finding a way to stop the toxic proteins from changing their structure, which would allow the lysosomesto effectively clear them from the brain. This would halt the chainreaction that causes the neurodegeneration associated withAlzheimer's.
"It's been long known that these modifications happen inlong-lived proteins, but no one has ever looked at whether thesemodifications could prevent the lysosomes from being able to breakdown the proteins," says Julian. "One way to prevent this wouldbe to recycle the proteins so that they are not sitting around longenough to go through these chemical modifications. Currently, nodrugs are available to stimulate this recycling – a process calledautophagy – for Alzheimer's disease treatment."
Restoring the body's ability to clear toxic Alzheimer's-inducingproteins from the brain is certainly not a new therapeutic strategy,and neither is focusing on the lysosomal system to achieve this. Thenew research does however offer a compelling hypothesis as to why lysosomesstruggle with clearing amyloid and tau, suggesting researchdirections for novel future therapeutic drugs.
The new study was published in the journal ACS Central Science.
Source: UC Riverside