Autophagy – when recycling goes awry

Autophagy – the neuron’s recycling system – seems to be impaired in Alzheimer’s disease. Oganelles that accept and degrade cell wastebecome clogged with debris and burst,spilling digestive enzymes that kill the cell.

An increasingly large body of evidence suggests a key role for neuronal autophagy in Alzheimer’s and other neurodegenerative diseases, including Parkinson’s.

Autophagy (“self-eating”) is the housekeeping system responsible for clearing and recycling proteins in every cell. The process degrades not only simple proteins, but entire organelles such as mitochondria. When autophagy is dysregulated, protein clearance also suffers.

The degradation vesicles – lysosomes – accept protein aggregates and damaged or worn-out organelles from another specialized vesicle, the autophagosome. Inside the lysosome, powerful enzymes break down the waste into protein components. Some are ejected from the cell, while some are released back into the cytoplasm where they can be reassembled as needed.

When the system becomes dysregulated, lysosomes don’t effectively clear these proteins. They become clogged, overextend, and burst. Enzymes that safely operate inside them then spread into the cytoplasm. They dissolve healthy organelles and eventually degrade the membrane, killing the cell.

To operate safely, enzymes must remain segregated within the lysosome. To operate effectively, they must work in an acidified environment. In Alzheimer’s and other neurodegenerative diseases, the lysosomal pH is raised toward neutral. This begins the domino effect that ends in cell death.

Some mutations associated with Alzheimer’s disease alter the lysosomal pH. Among these are mutations of the presenilin gene (PSEN1) and amyloid precursor protein (APP) genes. Down syndrome (trisomy 21) is another genetic disorder that inevitably leads to Alzheimer’s; it is also associated with defects in APP, as well as the lysosomal pH changes.

Beta amyloid is one cellular protein that lysosomes accept and process.

It would seem logical to assume that impaired autophagy would lead to an increase in the amount of amyloid within the cell, which could then released and aggregate into brain plaques. In fact, autophagosomes do both generate and contain amyloid. And autophagy induced by oxidative stress – which has also been implicated in Alzheimer’s – increases amyloid production.

However, impaired autophagy seems instead associated with reduced amyloid burden. A 2013 investigation found that it’s actually associated with fewer brain plaques – at least in mice (Cell Rep. 2013 Oct 17;5[1]:61-9). This investigation highlights the mysteries surrounding autophagy and Alzheimer’s.

There are no drugs in clinical trials that target autophagy. A few, however, are being investigated at the bench science level.

Illustration by Jeremy Swan

01/14/16 | By: MICHELE G. SULLIVAN

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