Dr. Klein's Reseach Interests: Molecular basis of Alzheimer's disease; apoptosis; signal transduction in brain development and plasticity

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.