In Alzheimer's and traumatic brain injury, neurons (red)
are killed off by the protein appoptosin
Below, steps in the cycle of apoptosis (cell death).
Hunting Neuron Killers in Alzheimer’s and TBI
Sanford-Burnham researchers discovered that the protein appoptosin prompts neurons to commit suicide in several neurological conditionsgiving them a new therapeutic target for Alzheimer’s disease and traumatic brain injury
by Heather Buschman
Dying neurons lead to cognitive impairment and memory loss in patients with neurodegenerative disordersconditions like Alzheimer’s disease and traumatic brain injury. To better diagnose and treat these neurological conditions, scientists first need to better understand the underlying causes of neuronal death.
Enter Huaxi Xu, Ph.D., professor in Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center. He and his team, for the past several years, study the protein appoptosin and its role in neurodegenerative disorders. Appoptosin levels skyrocket in the brain with conditions like Alzheimer’s and stroke, and especially following traumatic brain injury.
Appoptosin is known for its role in helping
the body make heme, the molecule that carries
iron in our blood (think “hemoglobin,”
which makes blood red). But what does heme
have to do with dying brain cells?
Xu and his group explain in a paper published
recently in the Journal of Neuroscience,
excess heme leads to the overproduction
of reactive oxygen species, which include
cell-damaging free radicals and peroxides,
and triggers apoptosis, the carefully regulated
process of cellular suicide.
This means that more appoptosin
and more heme cause neurons to die.
Not only did Xu and his team unravel this whole appoptosin-heme-neurodegeneration mechanism, but when they inhibited appoptosin in laboratory cell cultures, they noticed that the cells didn’t die. This finding suggests that appoptosin might make an interesting new therapeutic target for neurodegenerative disorders.
What’s next? Xu and colleagues are now probing appoptosin’s function in mouse models. They’re also looking for new therapies that target the protein.
“Since the upregulation of appoptosin is important for cell death in diseases such as Alzheimer’s, we’re now searching for small molecules that modulate appoptosin expression or activity. We’ll then determine whether these compounds may be potential drugs for Alzheimer’s or other neurodegenerative diseases,” Xu explains.
Putting a stop to runaway appoptosin won’t be easy, though. That’s because we still need the heme-building protein to operate at normal levels for our blood to carry iron. In a previous study, researchers found that a mutation in the gene that encodes appoptosin causes anemia. “Too much of anything is bad, but so is too little,” Xu says.
New therapies that target neurodegenerative disorders and traumatic brain injury are sorely needed.
According to the CDC, approximately 1.7 million
people sustain a traumatic brain injury each year.
It’s an acute injury, but one that can also lead
to long-term problems, causing epilepsy and
increasing a person’s risk for Alzheimer’s
and Parkinson’s diseases.
Not only has traumatic brain injury become
a worrisome problem in youth and professional
sports in recent years, the Department of Defense
calls traumatic brain injury “one of the signature
injuries of troops wounded in Afghanistan and Iraq.”
This study was funded by the U.S. National Institutes of Health (National Institute on Aging grants R01AG038710, R01AG021173, R01AG030197, R03AG034366, R01AG031893, AG5131, AG18440, R21AG038968; National Institute of Neurological Disorders and Stroke grants R01NS046673, R01NS054880) and the Alzheimer’s Association.
Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W, Xian B, Zhang X, Masliah E, Chen Q, Han JD, Bu G, Reed JC, Liao FF, Chen YG, & Xu H (2012). Appoptosin is a Novel Pro-Apoptotic Protein and Mediates Cell Death in Neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (44), 15565-15576 PMID: 23115192
Original article: http://beaker.sanfordburnham.org/2012/11/hunting-neuron-killers-alzheimers-tbi/