MISFN 42nd Annual Meeting, 2011
Keynote Speaker: Dr William Klein
Professor of Neurobiology & Physiology, and of Neurology
Northwestern University, Evanston, Illinois
Dr. William Klein,
Northwestern University
Formerly Director of Northwestern's Interdepartmental Graduate Program in Neuroscience, Dr. Klein currently is a member of the university's Cognitive Neurology and Alzheimer's Disease Center and the Nanoscale Science and Engineering Center. Dr. Klein serves on the editorial board of the Journal of Biological Chemistry and the scientific advisory board of Acumen Pharmaceuticals, a biotech he co-founded.
After graduating from MIT in biology, Dr. Klein carried out predoctoral studies in protein biochemistry at UCLA with Paul Boyer and postdoctoral studies in molecular neurobiology at the National Institutes of Health with Marshall Nirenberg . His research team at Northwestern has provided new insights into physiological synaptic signal transduction and cell biology, and more recently into the pathobiology of synapses in Alzheimer's Disease.
In a seminal contribution, Dr. Klein's team discovered that amyloid fibrils are not the only neurotoxins formed by Aβ peptide and likely not the most important ones: Aβ also generates small, soluble oligomers that are long-lived CNS neurotoxins capable of destroying the synaptic basis for memory and ultimately causing nerve cell death. Klein's team established that toxic oligomers (also known as ADDLs) are a major feature of Alzheimer's disease neuropathology through use of unique toxin-sensitive antibodies now under development for therapeutics. Their discovery that ADDLs are highly elevated in CSF of Alzheimer's patients offers promise as a diagnostic biomarker.
Mechanistic studies have revealed ADDLs to be gain-of-function ligands that attack particular synapses, provoking neuronal changes that account for both memory loss and major features of Alzheimer's disease neuropathology. As described in the Progress Report on Alzheimer's Disease published by the US Department of Health and Human Services, Aβ oligomers are now widely regarded as the primary cause of Alzheimer's nerve cell damage and memory loss. Investigations into toxic oligomers of Aβ have provided an archetypal mechanism now considered applicable to multiple diseases involving other fibrillogenic proteins (eg. Parkinson's disease, Type II diabetes, mad cow disease).
By explaining why Alzheimer's is a disease of memory and accounting for major pathological changes of Alzheimer's affected brain, ADDL toxicity provides a unifying molecular mechanism for pathogenesis, underscoring the importance of ADDLs as targets for clinical diagnostics and disease-modifying therapeutics.
Dr. Klein's research implicating small oligomeric species of Aβ (ADDLs) in the mechanism of Alzheimer's memory loss underlies new approcahes to effective early Alzheimer's treatments.