What Really Grinds Your Gears: How Oxidative Damage Contributes to Alzheimer’s Disease

Have you ever left the mall and failed to recall where you parked your car? Perhaps while running errands from your extended to-do list, you forgot to pick up your dry cleaning or that Netflix gift card and now you wont be able to watch the next episode of Bridgerton. These are all examples of forgetfulness, and although they are minor inconveniences, they do not heavily impact one’s day-to-day life. But what if one day you woke up and couldn’t remember your family members, or major life events like graduating, marriage, or becoming an aunt or uncle. The memories once held near and dear to your heart – now lost, and any attempt at recollection or recall is manifested as confusion and fear. These more severe memory impairments are all too common for over 432,000 Canadians above the age of 65 who are diagnosed with Alzheimer’s disease. 

The clock is a simple test to assess cognitive impairment in individuals suffering from neurological disorders such as Alzheimer’s Disease. When asked to draw a clock that displays the time 2:30, the left panel depicts a healthy individual’s illustration, the middle panel is an illustration drawn by an individual with mild cognitive impairment who forgot the time display while drawing the clock, whereas the right panel does not resemble a clock and was drawn by an individual with late-stage Alzheimer’s Disease

Alzheimer’s disease affects the brain and is characterized by the slow destruction of brain regions that are involved in memory development, recall, and overall thinking and comprehension skills. These regions are distributed throughout the entire brain and consist of thousands of cells called neurons, which are the basic building blocks of the brain. Imagine that your brain is built up of many different individual parts that seamlessly work together, not unlike a high-end mechanical watch. These different parts would coincide with the different brain regions that allow you to perceive emotions, help you store memories, recall past thoughts and ideas, while also allowing you to solve complex sudoku puzzles from your local newspaper. With time, the parts of an older mechanical watch may oxidize, develop rust, and corrode, which is like the oxidative damage that occurs in the brain as you age. Similar to how oxygen rusts the metal in an expensive watch to render it unusable, neurons can also produce by-products that cause oxidative damage, which destroys the cells and causes dysfunction. When neurons begin to die in this way, symptoms of Alzheimer’s disease may begin to arise.

Research from the University of Western Ontario led by Dr. Robert Cumming, PhD uncovered how the protein p66Shc promotes oxidative damage in neurons to progress Alzheimer’s disease. The protein p66Shc is present and inactive within neurons and the supporting cells of the brain called glia. However, when the protein p66Shc enters a specific part of brain cells called the mitochondria, it transforms the mitochondria into a toxic factory that produces a lot of oxidative by-products that can damage neurons and glia. This research study, published in 2018 in Scientific Reports demonstrated that when p66Shc is overexpressed in neurons that form memories, the mitochondria in these neurons begin to excessively produce oxidative by-products that damage and makes the neurons more vulnerable. Alternatively, when the researchers experimentally decreased the expression of p66Shc in glial cells, they noticed that the mitochondria in these supporting brain cells produced less oxidative by-products, leading to healthier brain cells. 

Think back to the mechanical watch. Rust can develop from a slow and natural reaction between the metal parts of the watch and oxygen in the air, similar to how the normal function of the mitochondria may produce low quantities of oxidative by-products. Alternatively, the presence of a catalyst such as saltwater or certain acids can speed up the formation of rust within that same watch and disable it sooner than expected. In this way, saltwater increases the speed that metal will rust, just like how the overactivity of p66Shc in neurons and glia can speed up the mitochondria’s production of oxidative by-products that that may damage these brain cells. When these oxidative by-products build up, neurons and glia become vulnerable and can no longer carry out their functions properly. These elevated levels of oxidative by-products produced in different brain regions brings about cellular dysfunction, which contributes to the clinical signs and symptoms of Alzheimer’s disease.   

The clinical signs of Alzheimer’s disease such as increased memory loss, confusion, and changes in mood and personality reflect the brain regions that are impacted by the disease. However, the oxidative damage that occurs in the brain at the cellular level puts much unneeded stress on neurons and glia and, more importantly, precedes the onset of these clinical signs. Research studies that focus on the cellular changes that precede the progression and clinical signs of the Alzheimer’s disease are crucial to fully understand the origins and develop therapeutic targets to treat the disease.