Why does a brain with dementia make a person forgetful?
or technically,
Differential α‑synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril‑induced toxicity.
[See Original Abstract on Pubmed]
Authors of the study: Esteban Luna, Samantha C. Decker, Dawn M. Riddle, Anna Caputo, Bin Zhang, Tracy Cole, Carrie Caswell, Sharon X. Xie, Virginia M. Y. Lee, Kelvin C. Luk
Why do we become more forgetful as we age? What makes some of us, who develop dementia, become more forgetful than others? Scientists at the University of Pennsylvania think the answers to these questions lie in physical changes that happen inside your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. as you get older. Esteban Luna, a neuroscience graduate student working in the laboratories of Drs. Virginia Lee and Kelvin Luk, set his focus on a particular area of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. called the hippocampus. The hippocampus is well-known for being the site of learning and memory in most mammals - from humans all the way to mice!
So what happens inside the hippocampus that researchers think could cause dementia? Esteban and other scientists think it all comes down to a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. not working as it normally does: it doesn’t fold correctly, and becomes “sticky” in this wrong shape. The proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. they think is the culprit in dementia is called alpha-synuclein (we’ll call it aSyn for short). The sticky, misfolded aSyn builds up inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles which makes them get sick and even die. When neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. don’t function properly they can’t communicate with the other cells around them, and whole regions (like the hippocampus) can end up being “short-circuited” or impaired! But how do you get lots of the messed up proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles? Scientists still don’t really know how that process begins in humans, but they’re trying to figure it out by artificially mimicking this proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. “build-up” in mice in the lab. In order to do that, scientists can begin by injecting a little bit of misfolded aSyn into the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Then, like a snowball effect, once there’s a little bit of the misfolded aSyn, the aSyn already inside the cell also begins to misfold and become sticky. As misfolded aSyn builds up, the cells get sicker and sicker, and can eventually die. What does this cell death have to do with memory? Well, Esteban Luna and colleagues think that when the build-up of misfolded aSyn leads to lots of cell death in the hippocampus (the memory center), we begin to experience problems with memory.
To test this idea, Esteban did just that: he injected a little bit of misfolded aSyn into the hippocampus of some mice and then looked at sections of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. after some time had passed to see what was happening to the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the hippocampus. One of the first things he noticed was that the different parts of the hippocampus looked different: some areas had lots of misfolded aSyn, some had less, and some parts had barely any! He noticed that this pattern also correlated with the patterns of cell death. In other words, places that had lots of misfolded aSyn were the same places where lots of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had died, and in places that had very little misfolded aSyn, most of the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles stayed alive.
Next, Esteban wondered if the different parts of the hippocampus had different amounts of normal aSyn to begin with, and if that might be why different areas responded differently to the “sticky” or toxic aSyn he was injecting. His idea was that if some neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had more regular aSyn to begin with, there would be more proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. available to misfold when he injected the sticky version. The hippocampus is normally made up of many different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, which ends up being really useful for researchers. This allowed Esteban to grow different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish and look at how much regular aSyn they had at baseline. When he grew the different kinds of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, he saw that the cells from the area with lots of misfolded aSyn and lots of cell death had lots of the aSyn to begin with. Remember, this is without any disease or injection of any kind. Similarly, the type of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles from the part of the hippocampus with very little misfolded aSyn and cell death had low levels of regular aSyn at baseline when grown in a dish. So what does all of this mean? It means that Esteban’s idea was right - neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have more of the regular aSyn to begin with are more susceptible to developing pathology (sticky, misfolded proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies.) and toxicity (cell death) than neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have less normal aSyn.
Finally, in order to find out if more initial aSyn actually causes the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to accumulate more misfolded aSyn during disease, Esteban performed a really cool experiment where he grew neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish that completely lacked any aSyn. Then, he gave these neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles a little bit of misfolded aSyn which normally snowballs to cause lots of buildup inside the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, and eventually leads to cell death. What did he find? There was almost no pathological buildup of misfolded aSyn inside the cell, and almost no cell death either! The toxic aSyn had no regular aSyn inside the cell to trigger misfolding of. This means that expression of regular aSyn inside the cells is required for the cells to develop pathology in response to the misfolded aSyn.
So what does this mean for humans with memory problems and dementia? For certain types of dementia that have buildup of misfolded aSyn and consequent cell death, Esteban’s work sheds light on some of the mechanisms of how that works and why some parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more susceptible to this damage than others. For example, certain areas of the hippocampus have cells that have lots of regular aSyn to begin with, and these are the cells that are susceptible to a toxic buildup of misfolded aSyn and eventual death. Hopefully, his work can help inform other kinds of research aiming to develop drugs that slow/stop the progression of dementia without harming other, healthy parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. in the process. Keep an eye out for all the cool work Esteban and his team at UPenn do in the future!
So what happens inside the hippocampus that researchers think could cause dementia? Esteban and other scientists think it all comes down to a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. not working as it normally does: it doesn’t fold correctly, and becomes “sticky” in this wrong shape. The proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. they think is the culprit in dementia is called alpha-synuclein (we’ll call it aSyn for short). The sticky, misfolded aSyn builds up inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles which makes them get sick and even die. When neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. don’t function properly they can’t communicate with the other cells around them, and whole regions (like the hippocampus) can end up being “short-circuited” or impaired! But how do you get lots of the messed up proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles? Scientists still don’t really know how that process begins in humans, but they’re trying to figure it out by artificially mimicking this proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. “build-up” in mice in the lab. In order to do that, scientists can begin by injecting a little bit of misfolded aSyn into the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Then, like a snowball effect, once there’s a little bit of the misfolded aSyn, the aSyn already inside the cell also begins to misfold and become sticky. As misfolded aSyn builds up, the cells get sicker and sicker, and can eventually die. What does this cell death have to do with memory? Well, Esteban Luna and colleagues think that when the build-up of misfolded aSyn leads to lots of cell death in the hippocampus (the memory center), we begin to experience problems with memory.
To test this idea, Esteban did just that: he injected a little bit of misfolded aSyn into the hippocampus of some mice and then looked at sections of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. after some time had passed to see what was happening to the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the hippocampus. One of the first things he noticed was that the different parts of the hippocampus looked different: some areas had lots of misfolded aSyn, some had less, and some parts had barely any! He noticed that this pattern also correlated with the patterns of cell death. In other words, places that had lots of misfolded aSyn were the same places where lots of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had died, and in places that had very little misfolded aSyn, most of the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles stayed alive.
Next, Esteban wondered if the different parts of the hippocampus had different amounts of normal aSyn to begin with, and if that might be why different areas responded differently to the “sticky” or toxic aSyn he was injecting. His idea was that if some neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had more regular aSyn to begin with, there would be more proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. available to misfold when he injected the sticky version. The hippocampus is normally made up of many different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, which ends up being really useful for researchers. This allowed Esteban to grow different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish and look at how much regular aSyn they had at baseline. When he grew the different kinds of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, he saw that the cells from the area with lots of misfolded aSyn and lots of cell death had lots of the aSyn to begin with. Remember, this is without any disease or injection of any kind. Similarly, the type of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles from the part of the hippocampus with very little misfolded aSyn and cell death had low levels of regular aSyn at baseline when grown in a dish. So what does all of this mean? It means that Esteban’s idea was right - neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have more of the regular aSyn to begin with are more susceptible to developing pathology (sticky, misfolded proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies.) and toxicity (cell death) than neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have less normal aSyn.
Finally, in order to find out if more initial aSyn actually causes the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to accumulate more misfolded aSyn during disease, Esteban performed a really cool experiment where he grew neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish that completely lacked any aSyn. Then, he gave these neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles a little bit of misfolded aSyn which normally snowballs to cause lots of buildup inside the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, and eventually leads to cell death. What did he find? There was almost no pathological buildup of misfolded aSyn inside the cell, and almost no cell death either! The toxic aSyn had no regular aSyn inside the cell to trigger misfolding of. This means that expression of regular aSyn inside the cells is required for the cells to develop pathology in response to the misfolded aSyn.
So what does this mean for humans with memory problems and dementia? For certain types of dementia that have buildup of misfolded aSyn and consequent cell death, Esteban’s work sheds light on some of the mechanisms of how that works and why some parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more susceptible to this damage than others. For example, certain areas of the hippocampus have cells that have lots of regular aSyn to begin with, and these are the cells that are susceptible to a toxic buildup of misfolded aSyn and eventual death. Hopefully, his work can help inform other kinds of research aiming to develop drugs that slow/stop the progression of dementia without harming other, healthy parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. in the process. Keep an eye out for all the cool work Esteban and his team at UPenn do in the future!
Want to learn more about memory problems in older adults? Check out Esteban Luna’s full paper here.
About the brief writer: Lyles Clark
Lyles is a fourth year student in Amelia Eisch’s lab. Lyles studies how neurons that are born after a traumatic brain injury contribute to pathology and hippocampal circuit dysfunction.