Research Assistant Professor of Biology
he/him
Current Research
Our lab investigates the role of genetic risk factors such as apolipoprotein E (apoE) in Alzheimer’s disease (AD). AD is a progressive neurodegenerative disease and the leading cause of dementia in the elderly, characterized pathologically by the loss of synapses and neurons as well as the formation of extracellular amyloid plaques and intracellular neurofribrillary tangles. The ε4 allele of apoE is the most important genetic risk factor for late-onset sporadic Alzheimer’s disease (LOAD). ApoE is a secreted glycoprotein that binds to a number of single-pass transmembrane receptors of the low-density-lipoprotein (LDL) receptor family, including apoER2 (LRP8), VLDLR, LDL receptor, LRP1 and TREM2 to mediate functions through intracellular signaling and endocytosis. In humans, apoE is polymorphic giving rise to three major alleles with frequencies of about 8% for ε2, 77% for ε3 and 15% for ε4 in the general population. In LOAD, apoE ε4 allele frequency increases to about 40% and individuals with one ε4 allele are 3 to 4 times more likely to develop AD than those without an ε4 allele. The goal of our lab is to understand the biochemical and functional relationship between apoE ligands and their respective receptors in the brain, ultimately to provide mechanistic understanding as to why the ε4 allele of apoE confers increased risk for Alzheimer’s disease and to provide plausible pathways to treatment.
Another area of investigation relates to the role of the LDL receptor family in neuronal migration and brain development. Like apoE, Reelin is a ligand for several LDL receptor family members and plays a critical role in determining the final positioning of neurons in the brain. Our work has uncovered key roles for Reelin in intracellular signaling as well as critical roles for cytoskeletal proteins to rearrange the neuronal cytoskeleton during neuronal migration. The goal of this area of research is to understand the role of ligands such as Reelin in the process of brain development and ultimately how alterations of this process may affect behavior in developmental diseases such as autism and schizophrenia.
Selected Publications
- Waxman H, Kankkunen M, Gupta A, Dowgiewicz M, Beffert U, Ho A (2025) Foxr1 deletion causes microcephaly and leads to cortical and hippocampal hypoplasia. Frontiers in Neuroscience 19:1589043.
- Lagani GD, Sha M, Lin W, Natarajan S, Kankkunen M, Kistler SA, Lampl N, Waxman H, Harper ER, Emili A, Beffert U, Ho A (2024) Beyond glycolysis: Aldolase A is a novel effector in Reelin mediated dendritic development. Journal of Neuroscience 44: e0072242024.
- Gallo CM, Kistler S, Natrakul A, Labadorf AT, Beffert U, Ho A (2024) APOER2 splicing repertoire in Alzheimer’s disease: Insights from long-read RNA sequencing. PLOS Genetics 20: e1011348.
- Henry S, Kistler SA, Lagani GD, Bartling CRO, Ozcelik D, Sereikaite V, Strømgaard K, Beffert U, Ho A (2023) Tight control of the APP-Mint1 interaction in regulating amyloid production. Brain Research 1817:148496.
- Omuro KC, Gallo CM, Scrandis L, Ho A, Beffert U (2022) Human APOER2 isoforms have differential cleavage events and synaptic properties. Journal of Neuroscience 42: 4054-4068.
- Gallo CM, Labadorf AT, Ho A, Beffert U (2022) Single molecule, long-read Apoer2 sequencing identifies conserved and species-specific splicing patterns. Genomics 114:110318
- Mota A, Waxman HK, Hong R, Lagani GD, Niu S-Y, Bertherat FL, Wolfe L, Malicdan CM, Markello TC, Adams DR, Gahl WA, Cheng CS, Beffert U, Ho A (2021) FOXR1 regulates stress response pathways and is necessary for proper brain development. PLoS Genetics 17: e1009854.
- Dillon GM, Tyler WA, Omuro KC, Kambouris J, Tyminski C, Henry S, Haydar TF, Beffert U, Ho A (2017) CLASP2 links reelin to the cytoskeleton during neocortical development. Neuron, 93:1344-1358.