“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell,” said study senior investigator Ralph Nixon, a professor in the Department of Psychiatry and the Department of Cell Biology at NYU Langone and director of the Center for Dementia Research at Nathan Kline.
“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons.”
This latest study published in the journal Nature Neuroscience online has traced the roots of neuronal damage characteristic of Alzheimer’s disease and the findings in contrast to what was previously thought.
In the past, it was believed that the critical first step toward the brain damage observed in Alzheimer’s disease was the formation of plaques containing protein amyloid beta outside of cells.
However, in their mice experiment, researchers at the NYU Grossman School of Medicine and the Nathan Kline Institute discovered that the dysfunction starts from inside the cells, particularly in the brain’s lysosomes.
These lysosomes are tiny sacs located inside every cell and filled with acidic enzymes. These enzymes are responsible for the routine breakdown, removal, and recycling of metabolic waste from daily cell reactions and diseases. Lysosomes are also responsible for the breaking down and disposing of a cell’s parts upon its death.
However, based on the researchers’ observations, some of these lysosomes grow in size when they combine with autophagic vacuoles that are filled with waste that had not broken down. Inside these vacuoles, as well, are earlier forms of amyloid-beta.
After fusing with the lysosomes inside the cells, the vacuoles would pool together like flowers, bursting out from the cells’ outer membranes and gathering around each nucleus.
The accumulated amyloid-beta would then form filaments inside the cell, as observed by the researchers in almost totally formed plaques within some damaged neurons.
The researchers have likewise discovered the cause of a cell’s waste disposal problems, a gene called PSEN1. This gene has long been associated with Alzheimer’s disease, but it is only now that the medical world is getting enlightened about its additional responsibility in causing the disease through lysosomal dysfunction.