by Mabel Tang
Alzheimer’s disease is the sixth leading cause of death in the United States [1]. One third of American seniors die with Alzheimer’s or dementia, and 5.8 million Americans live with the disease [2]. This number is projected to reach 14 million by the year 2050 [3]. Despite the large numbers of people affected by the disease, it has no cure.
What we do know, however, is that there are several causes of Alzheimer’s disease. Studies suggest that the accumulation of proteins such as alpha-beta peptides and the tau protein in the brain contribute to the development of Alzheimer’s [4]. These aggregated proteins most likely disrupt neural activity and other circuits that control and support learning and memory, resulting in the death of neurons. Alzheimer’s can also be hereditary, although deterministic genes, or genes that directly cause disease, make up a very small percentage of cases [5]. On the other hand, Alzheimer’s risk is increased through head injury, diabetes and obesity, and age [6].
Dr. Joanna Jankowsky, a professor of neuroscience, neurology, neurosurgery, and molecular and cellular biology at Baylor College of Medicine, is seeking to better understand this devastating disease by modeling it with specially engineered mice. When Dr. Jankowsky first started her Ph.D at the California Institute of Technology, she was studying models of learning and memory. However, after working with a neurosurgeon on models of epilepsy, she found what she considers “the ground truth of the human disorder... You have a whole population of patients who want research on their disease because it’s so traumatizing for their life and their families’ lives. [My research] became much more grounded in something that seemed worthwhile. I really liked learning and memory, but I loved doing things that were clinically relevant, and the easiest way was to study a disease of learning and memory, which is how I came to Alzheimer’s disease.”
Dr. Jankowsky’s lab seeks to understand age as a risk factor for Alzheimer’s, the genetics behind Alzheimer’s resilience, and the connection between Alzheimer’s pathology and resilience to the disease. According to Dr. Jankowsky, some patients who died cognitively healthy are found at autopsy with brains that should have caused dementia in their lifetime. To answer these questions, the lab uses mouse models, putting genes in and taking genes out of their genome to better emulate the conditions the lab wants to study. By engineering the mouse genome such that the mouse will develop Alzheimer’s-like pathology or taking out genes responsible for cognitive resilience to the disease, Dr. Jankowsky and her lab can see how the interactions of brain cell proteins affect the mouse’s cognitive behavior, and decipher if these alterations contribute to the development of Alzheimer’s.
Dr. Jankowsky’s lab has two electrophysiology rigs, used to record the electrical activity of single neurons or circuits in the acute brain slices of their genetically engineered mice. According to Dr. Jankowsky, it is used to specifically look at how adding a gene or taking a gene away can change a neuron’s function. Her lab also uses stereotaxic surgery, a form of surgery used to inject viruses that specifically inject a protein of interest to a specific cell population or circuit in the brain. Finally, there are special behavioral rooms used to test cognitive function in mice and examine if the gene manipulations are impacting the mice’s ability to learn and retain new information.
Dr. Jankowsky’s research is supplemented by the developments in Alzheimer’s research in recent years. Scientists have found an association between a buildup of plaques of the amyloid-beta protein in between neurons and abnormal accumulations of the tau protein in neurofibrillary tangles with the development of Alzheimer’s disease. The accumulation of beta-amyloid in between neurons disrupts cell function, while neurofibrillary tangles block neuronal communication in areas that control learning and memory [7]. According to Dr. Jankowsky, her lab has been able to treat this amyloid pathology in mice with signs of Alzheimer’s disease and rescue the mice’s cognitive impairment by turning genes off and on. Most recently, her lab has been working to study particular circuits that are affected early in Alzheimer’s development, such as the circuit responsible for ongoing recall of familiar environments. “One of the problems Alzheimer’s patients will have, in the beginning of the disease, is that they will often end up in places that are familiar, but they suddenly realize they don’t know how to navigate out of that place,” Dr. Jankowksy says. “ We’ve been able to show that one of the circuits that is affected early in Alzheimer’s disease may underlay that deficit.” The finding Dr. Jankowsky believes is most relevant to human applications, though, is a study she completed in which she combined two ways of attacking the amyloid-beta protein. “We got a better effect on cognitive recovery than we did with either [treatment] alone, show[ing] that combination treatment may be more effective than single treatment. My hope is that it will be soon be conveyed in human studies, where so far we have done one drug at a time and failed every time. I hope we get to a point where we start considering combination trials in human studies too.”
These developments in research could not have occurred without technological improvements from just the last ten years. “Our access to knowledge [and] our ability to do large experiments quickly has increased exponentially,” Dr. Jankowsky recalls. “Things have progressed tremendously even in just the last ten years.” Despite this progress, however, the lab still faces challenges. According to Dr. Jankowsky, funding is always a challenge. The process of applying for grants is tedious, and there is a possibility of waiting a very long time between the time of application and when funding is actually received. While the funding rates for Alzheimer’s research has increased significantly in the last twenty years, Dr. Jankowsky says that “[scientists are] constantly struggling to juggle grants and employment”. Aside from funding, Dr. Jankowsky says that there are certain fundamental questions that still have not been answered. She is using her $450,000 Zenith Fellows research grant from the Alzheimer’s Association to work on a particular protein called T-mem106B. This membrane resides in the cell’s lysosome, which is considered the “trash bin” of the cell, degrading and recycling proteins to be used by the cell. However, it is not known what T-mem106B does at the lysosome. The gene that encodes this protein was found in subjects who were cognitively normal at death but had a lot of amyloid plaques and neurofibrillary tangles in their brains. The lysosome is supposed to dispose of these aggregates, and, as Dr. Jankowsky explains, “if our gene is responsible for making the lysosome work better, those patients should have been cognitively resilient because the lysosome was working better and got rid of all those protein aggregates. But it’s just the opposite.”
Despite these obstacles, Dr. Jankowsky hopes to see a brighter future for Alzheimer’s research. While she considers her laboratory a “very small cog in a very large wheel of research” and a “small part of what needs to happen in order to impact society,” she says the ideal goal is an interventional treatment and a cure for the disease. However, she would also settle for preventative treatments. “We are telling people to go out and live healthier lives. Those are all true, but there are a lot of people midlife like me who aren’t going to exercise as much as we should or don’t eat or sleep properly and are putting ourselves at risk. I hope there is something out there for those of us who aren’t doing everything we can to protect our brain health later in life.” Out of her work, however, Dr. Jankowsky considers what she can do best toward the larger effort of Alzheimer’s research is training the next generation of scientists. “If the people who come out of my lab learn how to do research in a rigorous way and become better scientists than I am, then I would have succeeded. I think I have a greater impact on the future with the people I train than I do with the publications I put out now.”
References
[1] Alzheimer’s Association. Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures (accessed Oct 22, 2019).
[2] Alzheimer’s Association. Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures (accessed Oct 22, 2019).
[3] Alzheimer’s Association. Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures (accessed Oct 22, 2019).
[4] Mucke, L. Alzheimer’s disease. Nature [Online] 2009, 461, 895-897. https://www.nature.com/articles/461895a#citeas (accessed Feb 20, 2020).
[5] Mucke, L. Alzheimer’s disease. Nature [Online] 2009, 461, 895-897. https://www.nature.com/articles/461895a#citeas (accessed Feb 20, 2020).
[6] Mucke, L. Alzheimer’s disease. Nature [Online] 2009, 461, 895-897. https://www.nature.com/articles/461895a#citeas (accessed Feb 20, 2020).
[7] Brion, JP. Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol [Online] Oct 1998, 130-140. PubMed.gov. https://www.ncbi.nlm.nih.gov/pubmed/9748670 (accessed Oct 22, 2019).