Our Research

A unifying mechanism underlying multiple neurodegenerative diseases as a target for new drug discovery.

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 now comprises over six thousand articles. Our prior research has led to development of Sabirnetug, an AβO-selective monoclonal antibody that is in Phase 2 clinical trials by Acumen Pharmaceuticals, a biotech co-founded with colleagues Grant Krafft and Caleb Finch. Sabirnetug has the potential to be safer and more effective than Leqembi (Eisai/Biogen), an antibody that targets a large AβO proteoform was recently approved for AD therapeutics. New drug discovery experiments by our team focus on a novel theory that neurodegenerative diseases are caused by a common pathogenic mechanism that generates different toxins in different cells. We have found that a 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 using cell cultures, neuropathology, and behavioral investigations with Alzheimer’s models. This research involves collaborations with Professors Silverman and Ozdinler. Other drug discovery efforts in collaboration with Professors Silverman and Surmeier target a key step in the pathway by which AβOs stimulate formation of pathological tau, a phenomenon we discovered earlier. Additional research concerns development of active vaccines designed to prevent the buildup of AβOs, which the Director of Neuroscience at the NIA has called a “central toxic event in Alzheimer’s disease…”

Molecular mechanisms that link neurodegeneration and neurodevelopment.

We recently discovered that AβOs and hyperphosphorylated tau, which are widely studied for their roles in Alzheimer’s disease, are present during CNS development and then down-regulated. The transient AβOs appear to be a new class of neuropeptide regulators whose function is mediated by tau phosphorylation. Our discovery was made using embryonic chick retina, which expresses the same Aβ sequence as humans and is an outstanding system to study CNS development. New projects investigate how the function of Alzheimer’s-related pathways participate in building proper neurocircuitry, what mechanisms underlie the assembly of AβOs, and how the developing retina achieves a very remarkable spatio-temporal regulation of AβOs and phosphoTau molecules. Besides answering new and questions about neurodevelopment, this project should give new insights into what causes AβOs to re-appear in the Alzheimer’s-affected brain.

Structural biology and diagnostic brain imaging of neurotoxins that cause Alzheimer’s disease.

AβOs are protein neurotoxins that putatively 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 and biophysical assays. Our structural, imaging, and assay development research involves collaborations with Professors Kelleher, Anker, Dravid, Du, Wu, Kelly, Mrksich, and Meade.