Autophagy, Amyloid, and Alzheimer's Disease

Autophagy is the name given to a collection of housecleaning and recycling processes that take place within cells. Research indicates that more autophagy is a good thing, leading to fewer damaged cellular components and metabolic waste products lingering to cause issues. Most of the methods demonstrated to extend life in laboratory animals are linked to enhanced levels of autophagy, and artificially increasing levels of autophagy might form the basis for future medical therapies.

Here, however, researchers show that extracellular levels of amyloid in Alzheimer's disease are reduced in mice with deficient autophagy, which is not the expected result, but nonetheless makes sense in context:

Pathological hallmarks of Alzheimer's disease (AD) include the aggregation of amyloid beta (Aβ) peptides inside neurons and the accumulation of extracellular Aβ plaques. Previously, the mechanisms by which Aβ leaves neurons were unknown, and it has been controversial whether the intracellular or extracellular accumulation of Aβ plays a larger role in AD-associated symptoms.

[Researchers] crossed mice deficient in autophagy in forebrain neurons with transgenic animals that produce abnormally high levels of the Aβ precursor protein. They found that the offspring had far fewer extracellular Aβ plaques than the transgenic mice that showed normal autophagy. "We know that autophagy is the cleaning system within the cell. Our expectation was that if we delete autophagy, we would get more of the Aβ plaques outside the cell. But we saw the contrary, so we were really surprised by that, and we had to work hard to understand why."

In order to understand the reason that autophagy-deficient mice had fewer Aβ plaques, the researchers measured Aβ release from neurons isolated from the mice. They observed a drastic decrease in Aβ secretion, which led to accumulation of Aβ inside the cells. [This in turn] led to neurodegeneration and memory impairment in the mice, consistent with earlier reports "that intracellular Aβ is toxic, or is at least contributing to the toxicity" in neurons. "We have brought some light to the issue, but of course it is not known yet how the toxicity is mediated. That remains to be elucidated." But the question of whether intracellular versus extracellular Aβ accumulation mediates the effects of AD remains contentious. "The field is divided."

"What this study is telling us, too, is that one of the mechanisms that protects the cells is getting rid of the Aβ that's in the cells and putting it outside the cell. Sure, it may still be toxic under those conditions, but the real toxicity is being generated by its accumulation and disruption of intracellular processes."

Link: http://www.the-scientist.com/?articles.view/articleNo/37769/title/Autophagy-s-Role-in-Alzheimer-s/

Comments

The experimental data point in all directions, e.g. -

"The Polyphenol Oleuropein Aglycone Protects TgCRND8 Mice against Aß Plaque Pathology"
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071702
"...oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction..."

Too bad there is insufficient funding to clarify the conlicting results.

Posted by: Lou Pagnucco at October 14th, 2013 1:03 PM

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