Brain Detoxification—Part 3—Autophagy and the Synergistic Proteasomal Degradation System in Brain Detoxification

Summary

 

Welcome!

 

This is Ralph Sanchez and today I’ll be expanding on the last two episodes—#16 & #17—in this special brain detoxification series. This is the third or part three in that series.

 

In our last two brain detoxification episodes I described the pathways of beta-amyloid and tau protein transport and clearance from the brain, and in their degradation in the liver in what I describe as the liver-brain axis in Alzheimer’s disease.

 

Today I’ll provide an overview on two related and crucial mechanisms of clearing debris, eliminating pathogens and neurotoxic proteins within the neuron and brain—namely autophagy and a complimentary proteasome degradation pathway.

 

Autophagy

We’ll begin with autophagy which falters in aging and is significantly impaired in many age-related diseases such as cancer, cardiovascular disease, diabetes and neurodegenerative diseases such as Alzheimer's.

 

These age-related diseases directly impact cellular protein turnover and disposal which is largely dependent on autophagy and a proteasomal degradation pathway, termed the ubiquitin-proteasome pathway.

 

To keep this overview as simple as possible in light of the fact that all three forms of the autophagic machinery (macroautophagy, microautophagy, and chaperone-mediated autophagy ) and related pathways are very complex, I will for the most part only be describing here the role of macroautophagy with regard to the autophagy-lysosome pathway in waste recycling, removal and clearance.

 

Macroautophagy is the most studied and described type of autophagy and it is the very same one that most educators speak of when describing the role of dysfunctional autophagy in the risk for AD.

 

Now an important focus of today’s overview on autophagy is that it serves as an intracellular clearance mechanism of potentially toxic proteins such as beta-amyloid and tau protein that disrupt neuronal function and the integrity of our cognitive function in aging IF they are not appropriately turned over and degraded as needed.

 

Autophagy also mediates the degradation of pathogens (e.g., viruses, bacteria), the removal of damaged cellular organelles like the mitochondria, and the cellular removal and recycling of proteins derived from the degradation of these targets for a nutrient and energy supply.

 

The recycling of proteins and cellular organelles is a component in the regeneration of new proteins that serve as functional and structural substrates—e.g., cellular membranes and new organelles.

 

Indeed, autophagy is a vital mechanism in cellular homeostasis throughout our healthspan.

 

If your brain detoxification pathways are at their best, your odds of preventing dementia and living younger, longer are vastly improved.

 

Now much of the public awareness with regard to the role of beta-amyloid in the brain revolves around the notion that beta-amyloid protein eventually forms plaque—outside the neuron—in the extracellular environment.

 

And to that point, in the first episode (#16) of this brain detoxification series that focused on the transport and removal of beta-amyloid and tau protein from the brain, I gave an overview on the presence of beta-amyloid and tau protein in the extracellular fluid—the interstitial fluid—that is then funneled into the glymphatic system or transported across the blood brain barrier for removal from the brain.

 

Additionally, the amyloid precursor protein (APP) that traverses the membranes of the neuron and generates the very beta-amyloid peptides that can eventually aggregate into deposits in the extracellular environment is also present on membranes within the neuron.

 

APP is also present on mitochondrial membranes and the membranes of other intracellular organelles (e.g./ endoplas