Collapse of Cellular Skeleton May Trigger Neuron Death in Alzheimer’s
Scientists at the University of California, Santa Barbara, have opened new doors in the search for what happens to brain cells being destroyed in Alzheimer’s disease and related dementias.
“With dementia, the brain cells, or neurons, that you need for cognitive skills are no longer working properly. Then, they’re not even there anymore because they die. That’s what leads to dementia; you’re losing neuronal capacity,” said senior author Stuart Feinstein, Ph.D., co-director of UC Santa Barbara’s Neuroscience Research Institute.
For about 30 years, Feinstein has been studying the protein called “tau” through the use of test tube biochemistry and a variety of cultured cells as models. In healthy conditions, tau is found in the long axons of neurons that connect with their targets, usually far off from the cell body itself. Tau acts to stabilize microtubules – a vital part of the cellular cytoskeleton and necessary for many aspects of neuronal cell structure and function.
It has been known for some time that a tiny peptide named amyloid beta is involved in neuronal cell death and Alzheimer’s disease, although the exact mechanism for how it works has remained unknown. Recently, genetic evidence has shown amyloid beta requires tau to kill neurons; however, what it does to tau has been mysterious.
“We know amyloid beta is a bad guy,” said Feinstein. “Amyloid beta causes disease; amyloid beta causes Alzheimer’s. The question is how does it do it?”
He noted that most Alzheimer’s researchers would say that amyloid beta causes tau to become abnormally and excessively phosphorylated. This would suggest that the tau proteins get inappropriately chemically modified with phosphate groups. “Many of our proteins get phosphorylated,” said Feinstein. “It can be done properly or improperly.”
Feinstein and his students wanted to find the exact reasons for the presumed abnormal phosphorylation of tau in order to gain a better understanding of what goes wrong. “That would provide clues for drug companies; they would have a more precise target to work on,” said Feinstein. “The more precisely they understand the biochemistry of the target, the better attack a pharmaceutical company can make on a problem.”
Feinstein said that the team’s initial hypothesis suggesting that amyloid beta leads to extensive abnormal tau phosphorylation turned out to be not true. “We all like to get a curve ball tossed our way once in a while, right?” said Feinstein. “You like to see something different and unexpected.”
The team discovered that when they added amyloid beta to neuronal cells, the tau in those cells did not get overwhelmingly phosphorylated as predicted. Instead, they observed a complete fragmentation of tau within one to two hours of the cells’ exposure to amyloid beta. Within 24 hours, the cells were destroyed.
Feinstein explained that tau has multiple jobs, but its most understood job is to regulate the cellular cytoskeleton. Cells have a skeleton much like humans have a skeleton.
One major difference, however, is that human skeletons don’t change shape very quickly, whereas a cell’s skeleton is constantly shortening, growing, and moving. It must do this to help the cell carry out many of its important functions. The cytoskeleton is especially vital to neurons because of their great length.
Feinstein argues that neurons die in Alzheimer’s disease because their cytoskeleton is not working properly. “If you destroy tau, which is an important regulator of the microtubules, one could easily see how that could also cause cell death,” said Feinstein.
“We know from cancer drugs that if you treat cells with drugs that disrupt the cytoskeleton, the cells die,” he said. “In my mind, the same thing could be happening here.”
The study is published in the online version of The Journal of Biological Chemistry.
Source: University of California
Pedersen, T. (2018). Collapse of Cellular Skeleton May Trigger Neuron Death in Alzheimer’s. Psych Central. Retrieved on August 6, 2020, from https://psychcentral.com/news/2011/06/12/collapse-of-cellular-skeleton-may-trigger-neuron-death-in-alzheimers/26790.html