Behold PANTHOS, a Toxic Wreath of Perinuclear Aβ That Kills Neurons

From Alz Forum

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Nixon and colleagues discovered PANTHOS when studying the role of the autophagy/lysosomal system in Alzheimer’s. Scientists have become increasingly interested in the role of this degradation pathway in AD and other neurodegenerative diseases, but have been stymied tracking changes in autophagic lysosome in the brain

In Alzheimer’s disease, defective autophagy seeds Aβ fibrils around the nuclei of neurons, which then burst, leaving amyloid plaques in their wake. This is according to researchers led by Ralph Nixon and Ju-Hyun Lee of New York University, Orangeburg. In the June 2 Nature Neuroscience, they reported that in five mouse models of amyloidosis, poorly acidified lysosomes stuffed with Aβ distort the plasma membranes of neurons and form toxic rosettes around their nuclei. Dubbed PANTHOS, these flower-shaped blebs seed Aβ fibrils and leak proteases into the cytoplasm. The neurons eventually burst, leaving behind amyloid cores that tally with plaque load. PANTHOS, aka poisonous anthos, from the Greek for flower, occurs in AD brain tissue as well.

  • Aβ accumulates in lysosomes when they fail to acidify.
  • As the vesicles swell, they hijack Golgi and ER membranes.
  • Perinuclear rosettes of Aβ fibrils then form.
  • When neurons burst, the rosettes coalesce into amyloid plaques.

“This meticulously conducted work is a tour de force,” said George Perry, University of Texas, San Antonio. “It changes the paradigm by clearly showing that amyloid accumulation occurs within neurons and that aggregates come out after the neurons degenerate or die.”

Charles Glabe, University of California, Irvine, agreed. “This inside-out view has largely been ignored for at least 30 years, while the outside-in paradigm has dominated,” he told Alzforum. Glabe and others had previously proposed that intracellular Aβ kills neurons and creates plaques in the brains of people with mild cognitive impairment, though how this happened was a mystery (Mar 2013 conference newsGouras et al., 2000D’Andrea et al., 2001). “The issue of whether Aβ pathology starts from the inside-out, or outside-in, is one of the most important questions that needed to be resolved,” he said.

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