Here is a somewhat interesting article about Alzheimer's disease, but I guess it has also value for studies of ALS and Parkinson's disease.
Until the 1980' all cells in the brain that were big enough to be studied routinely were the neurons. Neurons are impressive cells because they are extremely long. The other cells were called the glue "glia" because they had no obvious functions. Neurons are also impressive because they can convey electrical and chemical signals over long distances. Neurons once mature, mostly do not divide, especially the ones with long axons. Other cells more conventionally divide every few days.
Those other cells, which compose half of the brain's cells, are receiving more attention. There are multiple types but normally they are there to assist neurons in their task. A simplified view tells that neurons are a sort of plumbing system and the glial cells are the real actors in the brain.
One of the glial cells, the astrocytes, seems to play important roles, and these roles may change depending on biological events such as stress or pathogen intrusion. When they enter the state called reactive state (M1), they kill neurons, in a similar manner that macrophages (white cells) kill infected cells.
In Alzheimer's disease, the shrinking of the brain which is the result of dying neurons and glia, is associated with aggregates of amyloïd proteins (Aβ). The study found that Aβ protein triggers autophagy in astrocytes. Autophagy is a cellular process involved in waste removal and recycling. Cells need new proteins every passing minute to function correctly, and the diet would never be able to provide protein building blocks at the required speed, so it is of the utmost importance for cells to recycle used proteins. There are several kinds of autophagy mechanisms in cells. Neurons being quite passive giant cells, autophagy is mostly assured by astrocytes.
Recycling proteins is not a clean job, it involves breaking proteins into smaller components (the metabolites or even amino acids) in a series of steps. Some of these intermediate components are toxic.
This article investigates the role of autophagy in astrocytes in the context of Alzheimer's disease (AD). Autophagy plays a crucial role in clearing Aβ so disrupting autophagy in astrocytes leads to increased Aβ plaques and cognitive decline in AD mouse models. Conversely, enhancing autophagy by over-expressing the LC3B pathway with a genetic therapy in astrocytes can reduce Aβ plaques and improve cognitive function.
It is believed by the authors that Aβ is toxic because it induces urea cycle activation in astrocyte as a compensatory mechanism to deal with the toxic effects of Aβ.. The urea cycle is a metabolic pathway that primarily occurs in the liver, but it can also be active in astrocytes. This pathway is involved in detoxifying ammonia, a toxic byproduct of amino acid metabolism.
Overall, this study provides evidence that targeting autophagy in astrocytes may be a promising therapeutic approach for AD. Understanding the relationship between Aβ, autophagy, and the urea cycle could potentially lead to new therapeutic strategies for AD. For example, targeting the urea cycle or autophagy pathways might be explored as potential approaches to reduce Aβ toxicity.