Our Research
Research Opportunities
Molecular mechanisms linking neurodegeneration and neurodevelopment.
We recently discovered that amyloid beta oligomers (AβOs) and hyperphosphorylated tau, which have been widely studied for their role in Alzheimer’s disease, are present for a short time during CNS development, a discovery made using embryonic chick retina as a model. The transient AβOs appear to be a new class of neuropeptide regulators whose function is mediated by tau phosphorylation. New projects investigate how proper neurocircuitry depends on these signaling mechanisms and how the transient expression of AβO and phosphoTau is developmentally regulated. Besides answering important questions about neurodevelopment, this projected is expected to give new insights into mechanisms that cause AβOs to re-appear in the aging, Alzheimer’s-affected brain. This project involves a collaboration with NU Professor Tiffany Schmidt.
Structural biology underlying why oligomers are toxic and how they can be used for diagnostic imaging and immunotherapeutics.
Amyloid beta oligomers, (AβOs) are peptide neurotoxins believed to instigate the brain damage underlying Alzheimer’s disease. Our proteomics and structural biology projects investigate the basis for the gain-of-function toxicity that emerges when Aβ peptides, which are normal brain metabolites, assemble into oligomers. Experiments involve AβO purification by a family of highly selective antibodies, including a therapeutic antibody now in a clinical trial by Acumen Pharmaceuticals, a company my colleagues and I co-founded. Our antibodies target distinct proteoforms of AβO, which show differing subunit structure and spatio-temporal expression. In related translational studies, we are developing proteoform-selective antibodies and synthetic megamolecules as probes for definitive Alzheimer’s diagnostics using MRI and PET imaging. This research involves collaborations with NU Professors Kelleher, Dravid, Mrksich, and Meade.
Drug discovery that targets a unifying mechanism underlying multiple neurodegenerative diseases.
Our team introduced and pioneered the hypothesis that AD is due to the neurological impact of toxic AβOs. The study of AβOs as a basis for the cause, diagnosis, and treatment of Alzheimer’s has become a mature field, with over 5000 articles published on AβOs, and an antibody (Leqembi, from Eisai) that targets a large AβO proteoform was recently approved for AD therapeutics by the FDA. New drug discovery experiments by our team now focus on a novel theory that different toxins, which cause multiple neurodegenerative diseases, are generated at the cellular level by the same pathogenic mechanism. Our recent findings support this theory — a single molecule, potentially a therapeutic drug, blocks buildup of different toxic proteins responsible for AD, ALS, and FTD. Studies of the mechanism and therapeutic effectiveness of this and other small molecules are under way. This research involves collaborations with NU Professors Ozdinler and Silverman.