Where Immunology Meets Neuroscience

When Dr. David Hansen was hired by Genentech (South San Francisco, CA) in 2011, he was given the freedom to decide what he wanted to research. Hansen narrowed down the host of possibilities as they related to his background in neuroscience, and he ultimately chose to explore the intricacies of neuroinflammation to discover its connections to neurodegenerative diseases.

At first, Hansen wanted to better understand the brain’s immune cells and the significant role they play. As his work focused more specifically on Alzheimer’s disease (AD), he became more acutely aware of how many people suffer from this neurodegenerative disease. There are approximately 6.5 million Americans living with AD, and for people age 65 and older that number is projected to increase to nearly 13 million by 2050.1 “The physical and emotional tolls of dealing with Alzheimer’s disease are tremendously challenging for patients, and even more so for many more millions of families and caregivers,” Hansen commented. This realization was especially poignant for Hansen when he later learned the genetic variant most associated with increasing a person’s risk of AD is present in his own family.

Understanding the ways to best prevent AD, or delay its manifestation, “will be of incredible value to my family and to society in general,” he said. Hansen's decision to conduct research on Alzheimer’s disease is also influenced by his religious beliefs. “Another important value to me is having the work that I do be beneficial to society," he said, "and that’s partly motivated by my faith which encourages us to be engaged in worthwhile endeavors that help the society in which we live."

At the start of Hansen’s research, it was assumed by most researchers that neurodegenerative diseases were partly caused by neuroinflammation. However, in his preliminary studies, Hansen’s research team was “unable to reproduce a lot of what had been published in the scientific literature,” he said. For example, the team “couldn't see any pronounced role for the proinflammatory signaling in causing neurodegeneration. Instead, we did see very strong evidence that the immune cells play a protective role and help prevent Alzheimer's disease pathology from accumulating,” Hansen recalls. The discovery of that protective role has changed the course of AD research for Hansen and many other researchers like him.

With the assistance of geneticists, the research team at Genentech began analyzing common gene variants found in the general population that affect AD development. In the process, they came to understand that several genes expressed by microglia, the brain’s immune cells, alter the risk of AD development. Hansen noted that researchers often struggle with cellular clarity when analyzing tissue samples due to the challenges of knowing how different cell types contribute to the overall transcriptomic data from frozen tissue. However, his team was able to develop a novel method for isolating multiple cell types from frozen brain tissues. They identified 66 genes differentially expressed in microglia from AD patients compared to normal microglia, including the well-known AD risk gene APOE.² The team also recognized multiple states of microglial activation and the disparate roles they play in the AD pathology.³ As a result, Hansen and his colleagues realized that they needed to focus their research even more on the role and functions of microglia.

To identify direct correlations between AD-related gene variants and microglial function, Hansen began studying the proteins encoded by these AD-associated genes and their molecular functions in hopes of developing a pharmacological intervention to halt AD development. The research team first studied the paired immunoglobulin-like type 2 receptor alpha (PILRA), a microglial inhibitory receptor that recognizes O-glycosylated proteins. In 2018, they published their discovery of a common variant in PILRA, a glycine-arginine substitution encoded in the gene that reduces the ability of PILRA ligands to bind properly and reduces AD risk. Thus, the alteration of a single amino acid in PILRA protects individuals from AD risk via reduced inhibitory signaling in microglia.⁴

Hansen’s current research also performs manipulation in animal disease models to better observe how molecules and pathways impact AD pathologies. TREM2 (triggering receptor expressed on myeloid cells 2) is another microglia-expressed gene associated with AD so the researchers experimented with deleting TREM2 in the PS2APP mouse model. They observed increased accumulation of toxic Aβ peptides which cause amyloid plaque formation and neuronal injury. Their findings also suggest that compaction of β-amyloid into dense plaques is a protective microglial activity and “may prevent AD or delay its progression.”⁵ This new perspective on AD and how it develops in the brain will allow scientists to make monumental steps toward knowing how to fight the development of the disease.

Though many family members of AD patients may fail to see a hope for an Alzheimer’s cure, Hansen sees the possibility of developing both a treatment for it and the ability to prevent it. That ray of hope has spurred Hansen’s eleven-year journey in Alzheimer’s research and his quest to make AD intervention a reality. That quest continued here at BYU as Hansen assumed his new role as an associate professor in the Department of Chemistry & Biochemistry in 2020. Along with three biochemistry graduate students and an array of undergraduate students, Hansen is enjoying researching and working with his students to find new pharmaceutical targets. "It's really rewarding for me to just be able to interact with them, mentor them, and help them develop into strong scientists," Hansen said. "It's also rewarding to be able to conduct my research and interact with students in an environment that embraces both faith and science."

Hansen is especially grateful for the significant contribution the research he and his colleagues at Genentech have made toward the prevention and treatment of AD while he was there. “It's quite realistic that within a decade or two we'll have some very effective drugs for AD,” Hansen said. “Having effective drugs will allow us to identify people who have Alzheimer's pathology accumulating in their brain 10 years before they actually develop dementia.” Future medicine will recognize the presence or signs of AD pathology before they are manifest as dementia, and put a halt to the development of the disease.

As Hansen continues his ongoing research at BYU, the combination of his optimism and long-term commitment to AD research will not only give hope to his own family, it will also change the lives of millions of people.

By Allison McArthur

1. “Alzheimer’s and Dementia: Facts and Figures,” Alzheimer's Association, 2020, https://www.alz.org/alzheimers-dementia/facts-figures.
2. Karpagam Srinivasan et al., “Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation,” Cell Reports 31, no. 3 (2020): 107843, https://doi.org/10.1016/j.celrep.2020.107843.
3. David V. Hansen, Jesse E. Hanson, and Morgan Sheng, “Microglia in Alzheimer’s Disease,” Journal of Cell Biology 217, no. 2 (2018): 459–472, https://doi.org/10.1083/jcb.201709069.
4. Nisha Rathore et al., “Paired Immunoglobulin-like Type 2 Receptor Alpha G78R Variant Alters Ligand Binding and Confers Protection to Alzheimer's Disease," PLOS Genetics 14, no. 11 (2018): 1–20, https://doi.org/10.1101/325936.
5. William J. Meilandt et al., “Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model,” Journal of Neuroscience 40, no. 9 (2020): 26, https://doi.org/10.1523/JNEUROSCI.1871-19.2019