Evidence mounts for alternate origins of Alzheimers disease plaques: Results could explain why drugs designed to remove amyloid deposits have failed to stop disease

A breakdown in how brain cells rid themselves of waste precedes the buildup of debris-filled plaques known to occur in Alzheimer’s disease, a new study in mice shows.

The field argued for decades that such plaques, containing the protein amyloid beta, built up outside of cells as a crucial first step toward the brain damage observed in Alzheimer’s disease. Led by researchers at NYU Grossman School of Medicine and the Nathan Kline Institute, the new study challenges this idea, known as the amyloid cascade hypothesis.

The lastest study findings argue instead 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.

Publishing as the cover article in the journal Nature Neuroscience online June 2, 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 at NYU Langone Health and Nathan Kline (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.

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