New generation of mouse models mimic progression of AD
Dr. Hui Zheng, director of the Huffington Center on Aging and professor of molecular and human genetics at Baylor College of Medicine, has been studying and researching Alzheimer's at BCM for more than 10 years. Her lab is currently using mouse models to zoom in on molecules that are known to play a role in the disease.
"We know what molecules play a role in Alzheimer's. What we don't know is exactly how they affect the onset and progression of the disease," Zheng said, who is also professor of neuroscience and molecular and cellular biology.
Focusing on genes responsible for plaque
One characteristic of Alzheimer's is the presence of beta-amyloid plaques and neurofibrillary tangles. Beta-amyloid plaques are protein fragments from amyloid precursor protein that build up between nerve cells in the brain. Neurofibrillary tangles are twisted bits of protein that normally functions to stabilize transport machinery inside the nerve cells. In Alzheimer's disease the protein is abnormally accumulated. Both the amyloid plaques and neurofibrillary tangles are used to make a diagnosis at the time of autopsy.
Zheng focuses on amyloid precursor proteins and presenilins which are two classes of genes that are responsible for beta-amyloid plaque formation. They are also genetically linked to early onset Alzheimer's disease.
"Most people are not genetically predisposed to have Alzheimer's, meaning it does not run in the family and their case is considered sporadic," Zheng said. "We believe sporadic cases have the same underlying mechanisms as genetic cases, so we are focusing on those two classes of genes to further investigate the pathology of the disease."
Models enable researchers to follow molecular pathway
Using what is called a knockout mouse model, Zheng and her colleagues are able to delete those genes and follow the molecular pathway.
Her research has led to the discovery that the amyloid precursor proteins play a role in cholinergic neurons, which undergo profound degeneration in Alzheimer's disease. This finding has helped Zheng and her colleagues further understand that amyloid precursor proteins contribute to synaptic dysfunction in Alzheimer's disease. This could potentially be a target for new treatments.
Researchers are also using knock-in mice models. They are able to introduce the genetic mutations that lead to Alzheimer's disease to mice. This allows researchers to see how expression, rather than overexpression, will induce amyloid plaques and neurofibrillary tangles.
"We are creating a new generation of mouse models that mimic the human condition. We are in the process of seeing how this affects the mice and at what stage does each occurrence correlate with the learning, memory and synaptic plasticity found in Alzheimer's disease," she said.
Getting behind the scenes
Researchers are also examining the role of presenilins, proteins that have been shown to possess multiple biological activities and are essential for processing amyloid precursor proteins. By using presenilins inhibitors, they have learned that presenilins are needed to activate Notch signaling, which is important for cell to cell communication and gene regulation mechanisms that control multiple cell processes during embryonic and adult life.
"These mouse models give us a unique opportunity to follow the progression of the disease. We can not go into the human brain or manipulate it to see the progression. We only get to see the end result," Zheng said. "These models allow us to get to the basics and understand what is going on behind the scenes at the molecule level."
Models for behavior
Researchers in Zheng's lab are also using these mouse models for behavior analysis. They are able to see what regions of the brain are in use for certain learned tasks, then compare that to human brains.
"The brains of our mice models are obviously quite different from our own brains, however we can still see that certain areas, like the hippocampus and amygdala, are activated when different tasks are learned," Zheng said. "We can also review brain activity during memory retrieval of short-term and long-term memories."
Anxiety, learning, memory
In the knock-in mouse models researchers are also looking at the neuronal circuitry linking stress and Alzheimer's disease.
"It is known that AD patients have anxiety and depression symptoms and the amygdala, which controls these emotions, is affected early on in Alzheimer's," Zheng said. "But this area has not been specifically studied because many other neurological and behavior issues affect the same area and it isn't specific to Alzheimer's."
Zheng said this is another road to explore to fully understand this disease. She and her colleagues are currently studying how reducing anxiety will affect learning and memory and how that might affect amyloid precursor proteins.
"This pathway is involved in some way, it may not be specific to Alzheimer's but it correlates with the disease," Zheng said. "Could it play an important role in delaying or preventing certain pathogenesis? We don't know yet but it is worth questioning."