Failing Autophagy and Mitophagy in Alzheimer's Disease

The processes of autophagy break down and recycle damaged or unwanted structures within cells. Mitophagy is the specialized form of autophagy that clears malfunctioning mitochondria. Mitochondria are the power plants of the cell, bacteria-like organelles with their own small genome. They replicate to make up their numbers, while mitophagy acts as a quality control mechanism to ensure correct function by culling worn and broken mitochondria. Unfortunately, mitophagy declines in efficiency with age, and this may explain much of the loss of mitochondrial function in cells in old tissues, because it allows increasing dysfunction in the mitochondrial population.

Mitochondria play a key role in the production of energy and balance of reactive oxygen species (ROS) within cells. Mitophagy, the selective breakdown and clearance of aberrant and dead mitochondria, is a regulatory process essential to promoting cellular health and maintaining healthy mitochondrial populations. As a person age, oxidative stress and cellular damage accumulate, and autophagic pathways can become overwhelmed. This is especially true in non-actively dividing cells such as neurons, and cortical degeneration is commonly observed in aging populations.

Alzheimer's disease (AD), a characteristic illness of aging, is associated with cognitive deficits, including loss of memory formation and increased loss of cortical mass. Furthermore, characteristic conglomerates of amyloid-β (Aβ) and fibrillary tangles of abnormally phosphorylated tau are observed within the brains of AD patients. Synaptic damage and defective mitophagy are early changes in disease progression, and aging plays a key role in synaptic damage, autophagy, and mitophagy in AD progression and pathogenesis.

In the past 20 years, the toxicity of these mechanisms has been studied extensively, and their role in neuronal death partially elucidated. The buildup of abnormal mitochondria is noted in AD neurons. More recently, studies have focused on the interaction between Aβ and tau on the components of mitophagy. Although some interactions between Aβ and tau and also Aβ and tau interactions with mitochondrial proteins and the components of mitophagy have been noted; the exact mechanisms and sequence of events leading to the genesis of AD have yet to be elucidated. Accumulation of damaged mitochondria, excessive mitochondrial fission, the buildup of ROS within cells, and compromised cellular health are all noted within neuronal populations in AD brains.

A major challenge in studies on the pathology of AD is identifying individuals with early-onset AD as the symptoms mimic what is normally expected in aging populations. Identification of the early events of AD within these populations can help elucidate the development of biomarkers and pathology in AD and outline the mechanisms by which symptoms occur. Further research could potentially develop mitophagy-based therapies to block or even reverse the adverse effects of AD.

Link: https://doi.org/10.3389/fnins.2020.612757

Comments

@CANonymity: I read about the SRF donor who died in car accident 42yo. Im always been concerned with all sorts of safety as my grandfather was. He worked at a place where they melted iron and there had been many accidents. He always looked for improvements. But died 59yo after he cut himself in leg with a chain saw. I totally agree with you that sometimes you should not use a manual saw even if it takes your days or weeks. Einstein said that with regarding the nuclear bomb solutions are not always more tech but less tech. But he sometimes had wrong. At wikipedia there's one example when he refused lifesaving surgery that is standard today and all takes: Einstein refused surgery, saying, "I want to go when I want. It is tasteless to prolong life artificially. I have done my share; it is time to go. I will do it elegantly."

Posted by: thomas.a at February 11th, 2021 9:20 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.