David V. Hansen
Office: C212 BNSN
Office Phone: 801-422-7241
BS, Brigham Young University (2000)
PhD, Stanford University Medical School (2006)
Postdoctoral Fellow, University of California San Fransisco (2011)
The Hansen Lab studies the cellular and molecular mechanisms of Alzheimer’s disease (AD) pathogenesis. Human genetic studies have identified many AD risk genes, but how these genes impact physiological processes in the brain is not well understood. By studying the molecular function of proteins encoded by AD risk genes, our research aims to define key cellular processes that either protect against or contribute to AD pathogenesis.
The majority of AD risk genes are preferentially expressed by microglial cells, indicating that microglial dysfunction is a key factor underlying AD pathogenesis. Microglia are the brain’s resident immune cells, with macrophage-like properties. Alzheimer’s disease (AD) develops in the aged brain when protective microglial functions such as debris clearance and nerve cell maintenance become compromised. TREM2, a microglia-expressed AD risk gene, encodes a cell-surface receptor essential for the microglial response to damaged neural cells. Mutations in the TREM2 protein that reduce TREM2 signaling activity are associated with elevated AD incidence and faster AD progression. Therefore, pharmacological approaches that enhance TREM2-driven microglial activation may prevent AD development or slow AD progression.
While the function of TREM2 is somewhat understood, many other AD risk genes have not been functionally characterized. Our research aims to define the biochemical properties, molecular interactions, and cellular functions of proteins encoded by AD risk genes, particularly those expressed in microglial cells. In addition, we use -omics approaches to profile microglial cells in normal, neurodegenerative, or inflammatory conditions and understand how microglial activation profiles relate to AD pathology in mouse AD models and human AD tissues. Finally, we perform genetic or pharmacological manipulations in cellular and animal AD models to observe how our proteins and pathways of interest impact AD pathologies. Studying the function of microglia-expressed AD risk genes in normal and disease settings will reveal how microglial cells protect neurons from AD pathology and will identify new molecular targets for therapeutic intervention.
Microglial Blockade of the Amyloid Cascade: A New Therapeutic Frontier (Book chapter). Hansen DV, Cullimore BK, Johanson JC, Cheng W. Alzheimer’s Disease: Recent Findings in Pathophysiology, Diagnostic and Therapeutic Modalities, Royal Society of Chemistry (2022).
Microglia in Alzheimer’s Disease (Review). Hansen DV, Hanson JE, Sheng M. Journal of Cell Biology 217:459-472 (2018).
TREM2, Microglia, and Neurodegenerative Diseases (Review). Yeh FL, Hansen DV, Sheng M. Trends in Molecular Medicine 23:512-533 (2017).
TREM2 restrains the enhancement of tau pathology and neurodegeneration by ß-amyloid pathology. Lee S-H, Meilandt WJ, Xie L, Gandham VD, Barck KH, Ngu H, Rezzonico M, Imperio J, Lalehzadeh G, Huntley MH, Stark KL, Foreman O, Carano RAD, Sheng M, Easton A, Friedman BA, Bohlen CJ, Hansen DV. Neuron 109:1283-1301 (2021).
Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Srinivasan K, Friedman BA, Etxeberria A, Huntley MA, van der Brug MP, Foreman O, Paw JS, Modrusan Z, Beach TG, Serrano GE, Hansen DV. Cell Reports 31:107843 (2020).
Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the Aß42:Aß40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer’s mouse model. Meilandt WJ, Ngu H, Gogineni A, Lee S-H, Lalehzadeh G, Srinivasan K, Imperio J, Wu T, Weber M, Kruse AJ, Stark KL, Chan P, Kwong M, Modrusan Z, Friedman BA, Elstrott J, Foreman O, Easton A, Sheng M, Hansen DV. Journal of Neuroscience 40:1956-1974 (2020).
Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease. Rathore N, Ranjani Ramani S, Pantua H, Payandeh J, Bhangale T, Wuster A, Kapoor M, Sun Y, Kapadia SB, Gonzales L, Zarrin AA, Goate AM, Hansen DV, Behrens TW, Graham RR. PLoS Genetics 14(11):e1007427 (2018).
Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PCG, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV. Cell Reports 22:832-847 (2018).
Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD, Appling LL, Borneo J, Poon C, Ho T, Cai F, Steiner P, van der Brug MP, Modrusan Z, Kaminker J, Hansen DV. Nature Communications 7:11295, doi: 10.1038/ncomms11295 (2016).