Long before the plaques
For decades, scientists have argued that extracellular accumulation of amyloid plaques triggers brain damage characteristic of Alzheimer's disease. A new study led by researchers at NYU's Grossman School of Medicine and the Nathan Klein Institute challenges this hypothesis of an extracellular amyloid cascade. They showed that the damage to neurons characteristic of Alzheimer's disease begins inside cells long before amyloid plaques are fully formed. The study was published online in the journal Nature Neuroscience.
Using mouse models, the researchers identified the root cause of the developing changes – the disruption of the lysosomes. These are organoids filled with acidic enzymes that break down, recycle and remove waste from cellular metabolism. Lysosomes also play a key role in the destruction and disposal of the cell's own enzymes when it naturally dies.
The group observed a decrease in acidic activity inside the lysosomes of mouse cells as damage associated with Alzheimer's disease. Imaging tests developed at New York University to track the removal of cellular waste have shown that some lysosomes of brain cells increase when they merge with autophagic vacuoles filled with waste that could not be broken down. These autophagic vacuoles also contain earlier forms of beta-amyloid.
In the neurons that were most severely damaged and, as a result, doomed to early death, vacuoles combined into "floral" patterns, bulging out of the outer membranes of cells and accumulating around the nucleus. Clusters of beta-amyloid formed filaments inside the cell – another sign of Alzheimer's disease. The researchers observed almost completely formed plaques inside some damaged neurons.
These new findings change the fundamental understanding of how Alzheimer's disease progresses; they also explain why so many experimental treatments designed to remove amyloid plaques have failed to stop the progression of the disease – because brain cells are already damaged before the plaques are fully formed outside the cell. Thus, future treatments should be aimed at correcting lysosomal dysfunction and restoring the balance of acid levels in brain neurons.
The image obtained using fluorescence microscopy shows "flower" vacuoles in the neurons of a mouse with Alzheimer's disease.
Researchers are already working on experimental treatments for lysosomal dysfunction.
A recent study by a group of New York University in Langone, published in the April issue of the journal Science Advances, revealed one of the causes of problems with the disposal of cell waste - the PSEN1 gene. It is already known that this gene causes Alzheimer's disease, but its specific role in the occurrence of the disease through lysosomal dysfunction has become clear only now. The work also showed that damage to neurons in a mouse model of Alzheimer's disease can be reversed by restoring proper acid levels in lysosomes.
J.-H. articles.Lee et al. Fault autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aß in neurons, yielding senile plaques published in the journal Nature Neuroscience; article P.Lie et al. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function published in the journal Science Advances.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Neuroscience News: Evidence Mounts for Alternate Origins of Alzheimer's Disease Plaques.