Molecular Biology, Neuroscience
Our team is helping lead the way toward a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease. Alzheimer’s is a $200 billion a year epidemic that will confront virtually all families. In an early breakthrough study, we introduced the idea that neuron damage leading to AD is instigated by small toxic oligomers of the Aβ peptide. This new idea emerged from our discovery that oligomers are potent CNS toxins that rapidly destroy synaptic memory mechanisms. Our seminal paper (MP Lambert et al, PNAS 95:6448-6453, 1998) has been cited over 2500 times (Google Scholar). Since then, we have collaborated internationally to publish more than 100 papers investigating the oligomer hypothesis and how it might lead to mechanism-based diagnostics and therapeutics. Soluble Aβ oligomers, rather than plaques, are now widely regarded as triggering the neuron damage that causes dementia (see e.g., the review in Nature by Schnabel “Little Proteins, Big Clues,” Nature, 475, S12-14, 2011). Toxic Aβ oligomers have provided a structural archetype, moreover, for cytotoxins germane to over two dozen diseases of protein misfolding (including diabetes, Parkinson’s, and prion diseases).
Our ongoing research is highly collaborative and concerns five areas. (1) Structural biology. State-of-the-art facilities at CLP are being used to discover the molecular organization of toxic oligomers. Structure is poorly understood because of the difficulty in characterizing dynamic populations of oligomers in extremely dilute solutions. Approaches include unique native protein mass spectrometry and single molecule analysis using TIRF microscopy. (2) Cell and molecular mechanisms. How neuron damage is triggered by AβOs is being investigated in brain and stem cell culture systems. Experiments carried out with the help of BIF focus on early steps in the toxic mechanism. These include binding to toxin receptors, disrupted trafficking of ion channels and GPCRs, and altered signaling pathways. (3) Etiology. What causes AβOs to build up in AD is a major unknown. We are taking new approaches using non-transgenic models to investigate metabolic factors such as diabetes, hypercholesterolemia, and lysosome dysfunction. (4) Diagnostics. Because they appear early in disease and instigate the path to dementia, AβOs provide an optimal target for diagnostics. Ultrasensitive assays for clinical chemistry are being developed along with unique approaches to brain imaging by PET and molecular MRI using the resources of CAMI. (5) Therapeutics. Therapeutic antibodies are nearing clinical trials due to partnering between pharma and Acumen, a biotech built on our past work. New programs for drug discovery focus on peptides that attach to Aβ (to stop AβO formation), on insulin signaling (to block AβO toxicity), and on use of nanoscale synaptic membrane mimetics for high throughput screening (to obtain compounds that prevent AβO binding to toxin receptors).