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William Klein




Regions(s): Cellular and Molecular Neuroscience

Research interest(s): Molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease

Research Summary

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 $250 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 3500 times (Google Scholar; see e.g., the review in Nature by Schnabel “Little Proteins, Big Clues,” Nature, 475, S12-14, 2011). Since then, we have collaborated internationally to publish more than 100 papers (with over 16,000 citations) investigating the oligomer hypothesis and how it might lead to mechanism-based diagnostics and therapeutics. According to Eliezer Masliah, Director of Neuroscience for the National Institute on Aging, “Progressive accumulation of amyloid beta oligomers has been identified as one of the central toxic events in AD.” Soluble Aβ oligomers, rather than plaques, are now widely regarded as triggering the neuron damage that causes dementia. Toxic Aβ oligomers have provided, moreover, a structural archetype 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) Therapeutics. AβOs are excellent targets because of their early role in causing brain damage. Therapeutic monoclonal 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 insulin signaling (to block AβO toxicity) and on high throughput screening using nanoscale synaptic membrane mimetics (to obtain compounds that prevent AβO binding to toxin receptors). (2) Diagnostics. AβOs provide an optimal target for diagnostics because they appear early in disease and instigate the path to dementia. Ultrasensitive assays for clinical chemistry are being developed along with unique approaches to brain imaging by PET and molecular MRI. (3) Etiology. The cause of AβO build up in in late-onset AD is a major unknown. We are taking new approaches using non-transgenic models to investigate metabolic factors such as high sugar and fat diets associated with diabetes and hypercholesterolemia. (4) Cell and molecular mechanisms of memory loss. How neuron damage is triggered by AβOs is being investigated in brain cell culture systems and animal models. Experiments 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. (5) Structural biology. State-of-the-art facilities are being used to discover the molecular organization of synthetic and brain-derived toxic oligomers. AβO structure is still poorly understood because of the difficulty in characterizing dynamic populations of oligomers in extremely dilute solutions. Approaches include cryoEM and unique native protein mass spectrometry.

Collaborators include Disterhoft, Geula, Meade, Dravid, Luan, Kelleher, Mirkin, and Van Duyne (Northwestern); De Felice and Ferreira (Federal University, Rio de Janeiro); Sebollela (Sao Paolo); Mori and Tomiyama (Osaka); Cuello (McGill); Giacobini (Geneva); Nordberg (Karolinska); Gandy (Mt. Sinai); Sligar (University of Illinois, Urbana-Champagne).


Selected Publications