Arguing for Amyloid-β Aggregates to First Originate Inside Cells

Researchers here suggest that the amyloid-β aggregates characteristic of Alzheimer's disease first originate inside cells, and are connected with lysosomal dysfunction. Only later do the better studied toxic extracellular aggregates form. This is not the first group to point out that intracellular amyloid-β may be important. It is early days for this line of research, and quite unclear as to how this might change strategies aimed at disrupting the early stages of the condition, prior to symptoms, a period of years in which amyloid-β aggregates are accumulating slowly over time.

Study findings argue that neuronal damage characteristic of Alzheimer's disease takes root inside cells and well before these thread-like amyloid plaques fully form and clump together in the brain. The study traced the root dysfunction observed in mice bred to develop Alzheimer's disease to the brain cells' lysosomes. These are small sacs inside every cell, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, as well as from disease. Lysosomes are also key, researchers note, to breaking down and disposing of a cell's own parts when the cell naturally dies.

As part of the study, researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured in the disease. Imaging tests developed to track cellular waste removal showed that certain brain cell lysosomes became enlarged as they fused with so-called autophagic vacuoles filled with waste that had failed to be broken down. These autophagic vacuoles also contained earlier forms of amyloid beta. In neurons most heavily damaged and destined for early death as a result, the vacuoles pooled together in "flower-like" patterns, bulging out from the cells' outer membranes and massing around each cell's center, or nucleus. Accumulations of amyloid beta formed filaments inside the cell, another hallmark of Alzheimer's disease. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons.

"Previously, the working hypothesis mostly attributed the damage observed in Alzheimer's disease to what came after amyloid buildup outside of brain cells, not before and from within neurons. 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."


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