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.
- 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, March 22, 2017. PMID: 28285824.
- Wasser CR, Masiulis I, Durakoglugil MS, Lane-Donovan C, Xian X, Beffert U, Agarwala A, Hammer RE, Herz J. (2014) Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning. Science Signaling 7(353):ra113. PMID: 25429077.
- Beffert U, Dillon GM, Sullivan JM, Stuart CE, Gilbert JP, Kambouris JA, Ho A (2012) Microtubule plus-end tracking protein CLASP2 regulates neuronal polarity and synaptic function. Journal of Neuroscience, 32:13906-13916. PMID: 23035100.
- Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM, Herz J. ApoE receptor 2 controls neuronal survival in the adult brain. Current Biology (2006) Dec 19;16(24):2446-52. PMID: 17174920.
- Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD, Li WP, Adelmann G, Frotscher M, Hammer RE, Herz J. (2005) Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47(4):567-79. PMID: 16102539.
- Beffert U, Weeber EJ, Morfini G, Ko J, Brady ST, Tsai LH, Sweatt JD, Herz J. (2004) Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. Journal of Neuroscience 24(8):1897-906. PMID: 14985430.
- Assadi AH, Zhang G, Beffert U, McNeil RS, Renfro AL, Niu S, Quattrocchi CC, Antalffy BA, Sheldon M, Armstrong DD, Wynshaw-Boris A, Herz J, D’Arcangelo G, Clark GD. Interaction of reelin signaling and Lis1 in brain development.
Nature Genetics (2003) Nov;35(3):270-6. PMID: 14578885.
- Beffert U, Morfini G, Bock HH, Reyna H, Brady ST, Herz J. (2002) Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta.
Journal of Biological Chemistry 277(51):49958-64. PMID: 12376533.
- BI 203 Cell Biology