“Do you already have Alzheimer’s?”
This is the question Brian Ackley, associate professor of molecular biosciences at the University of Kansas, poses to the KU student body, a collectively young demographic rarely associated with the disease.
People only start asking this about themselves or loved ones when symptoms begin to show. But what if a student was already primed to develop Alzheimer’s disease and didn’t know it?
At the Ackley lab, scientists are investigating whether early exposure to triggers that initiate brain cell damage could predispose humans to develop Alzheimer’s. If this is the case, doctors could potentially test whether someone is prone to develop the disease and treat it before damage is done.
According to Ackley, Alzheimer’s is probably just one of a constellation of symptoms kickstarted by the progressive degeneration of synapses. The synapse is the space between two neurons in the brain where the cells communicate with each other and store information, like memories.
Synapse loss itself is not abnormal. The human brain adds and prunes new synaptic connections every day. The brain also naturally loses synapses with age as the body’s ability to maintain those connections weakens.
“In diseased states, this process of synapse subtraction is hyperactive or accelerated, causing more widespread and more noticeable symptoms of synapse degeneration, like Alzheimer’s,” Ackley said.
According to Ackley, most dementia and Alzheimer’s cases are late-onset, and many factors contribute to developing the diseases.
One of the lab’s working hypotheses is that once neurons experience a certain stress threshold, their self-care mechanism is overwhelmed or quits, creating a detrimental environment that eventually destroys synapses. Through the Ackley lab’s experiments on roundworms called C. elegans, researchers found that cumulative neuron stress throughout the animal’s life led to abnormal synapse degeneration. This is similar to what is seen in patients with disorders like frontotemporal dementia, Ackley said.
Scientists want to know whether exposing a young C. elegans to that critical threshold of stress all at once, instead of progressively with age, can prime it to also later develop Alzheimer’s-like symptoms. In theory, if there is a common, fundamental process behind abnormal synapse degeneration, Ackley said, someone as young as the typical KU student could be screened for the general markers of deterioration and diagnosed before they are symptomatic. The researchers further hypothesized they could tap into this fundamental process and stop or reverse the synaptic damage.
“There’s some reasons to think that we can do that. We just haven’t done that in my lab yet,” Ackley said.
The roundworms that experienced abnormal synapse loss in a similar model to frontotemporal dementia were forced to continuously replicate a mutated protein called Tau, which is also found in affected patients. Normally, Tau helps our neurons maintain their shape. However, as the worms continually produced the mutated Tau, the proteins clustered together, severely stressing the cells and destroying the synapses.
“We know that when we express mutated Tau in the worms, we see rapid neurodegeneration. When we inject the worms with Wildtype (normal) Tau, we see regular neurodegeneration associated with age,” said Wendy Aquino Nunez, a doctoral student in the Ackley lab. “In young people, we just haven’t accumulated enough misbehaving Tau clusters to cause abnormal synapse degeneration. But we all have the potential for developing Alzheimer’s and dementia.”
According to Aquino, it’s possible the Tau clusters stress neurons to the point that they produce more byproducts of their usual activities, called reactive oxygen species, or ROS.
ROS is like the bits of trash a student produces throughout their day, from waking up and going to class, to coming home and sleeping. A cell, under stress, is like a roommate during midterms, maybe producing more trash than usual. In a healthy neuron, much like a healthy living situation, the different residents of the cell clean up after themselves and each other. But if the stressed roommate is producing too much trash, this can prompt the other residents to fall behind or give up cleaning, leading to a dangerously messy house.
“ROS is the fuel that accelerates synapse degeneration,” Ackley said. “Normal synapse pruning is like a controlled burn. If you were to do an uncontrolled burn in a forest, with too much ROS, and it causes a forest fire, that is AD (Alzheimer’s disease).”
To investigate the culpability of ROS for “forest fire” synapse degeneration, Jennifer Amrein, another doctoral student in the lab, exposed younger roundworms to the same stress threshold that Aquino’s group eventually accumulated. The result? When Amrein’s “tween” C. elegans, as Aquino coined them, grew up, they underwent rapid synapse degeneration.
“Thereby suggesting that this stress, during early stages of development, could prime you to be neurodegenerative later in life, even if you don’t experience the stress through Tau,” Amrein said.
Although these studies help scientists better understand the development of neurodegenerative diseases, including Alzheimer’s, Ackley, Aquino, and Amrein clarified that their work on roundworms could not be immediately applied to humans. It will be up to future generations of researchers to build on the lab’s discoveries and eventually help patients.
But behind the cautious optimism, Ackley said the lab strives to provide people with hope.
“Is there a reason to hope from C. elegans? Does that hope translate into other models of AD (Alzheimer’s disease), like in humans?” Ackley said. “If it does, it’s plausible that we might have some of those chemicals that can treat patients already sitting around on the shelf.”