<strong>Cell and structural biology of Alzheimer’s disease; memory-linked synapse structure and signal transduction</strong>
Developing neurons make a quadrillion synapses, providing our brains their enormous computational power. These synapses degenerate in Alzheimer's-afflicted neurons, neurons die, and all mental capacity is lost. To discover molecules that make synapses in development and destroy them in Alzheimer's disease is the purpose of our group's research.
Experiments several years ago led us to a novel molecule we think likely to cause Alzheimer's synaptic degeneration and nerve cell death (Lambert et al, 1998). We call this neurotoxic molecule an "ADDL." ADDLs are small, soluble oligomers of the peptide Aß. ADDLs almost instantly block LTP, a classic model for synaptic plasticity and memory. Subsequently, they cause nerve cell death by apoptosis. Gene knockouts show ADDLs act through a signal transduction pathway involving Fyn, a protein tyrosine kinase others have discovered is involved physiologically in LTP and developmental apoptosis and is overexpressed in Alzheimer's disease. We now know that ADDLs occur at high levels in AD-affected brain (Gong et.al., 2003), giving clinical validation to our theory. ADDLs may one day provide a basis for discovery of new drugs to combat Alzheimer's, a devastating disease that afflicts over four million people in the United States.
Our experimental approach is interdisciplinary and has been enhanced by close collaborations with other laboratories at Northwestern and throughout the country. Recent students have developed new electron microscope methods to image the creation of synaptic junctions; created monoclonal antibodies to indentify transient membrane proteins involved in synaptogeneiss; introduced computer-aided video-microscopy to discover signals that control the movement of growth cones; used confocal laser immunofluorescence microsopy to localize Alzheimer's-associated cytoskeletal molecules in developing axons; applied in vitro mutagenesis to study trafficking of an Alzeimer's-associated membrane protein; introduced cloned human nerve cells to indentify molecules underlying mechanisms of nerve cell death; developed organotypic cultures of adult mouse brain as a model for Alzheimer's pathogensesis; used atomic force microscopy to characterize ADDL structure; developed flow cytometry and chemical crosslinking methods for ADDL receptor discovery; invented a process to modify cytoplasmic protein function by delivering antibodies into living cells; engineered and transfected inducible trans-gene into nerve cell lines to discover targets and functions of specific protein tyrosine kinases; developed conformation-sensitive anti-bodies to detect ADDLs at ultra-low levels; used confocal immunofluorescence imaging to reveal the impact of ADDLs on synaptic memory-gene expression.
Our discovery of ADDLs has been widely acclaimed in scientific publications, with the original report in the Proceedings of the National Academy of Sciences cited more than 700 times. The ADDL story has also received broad coverage in popular press and electronic media—locally, nationally and internationally.
Is Alzheimer's a Form of Diabetes? TIME Thursday, Oct. 18, 2007 ,
Researchers Deem Alzheimer's a Type 3 Diabetes Chicago Tribune 11/27/07
Toxic Proteins That Interfere With Memory… USA Today
New Test Could Detect the Start of Alzheimer's (PDF) The Times (London) 02/01/2005