Synaptic Attack by ADDLs: A Mechanism for Memory Loss

These experiments will examine how a class of molecules, ADDLs, detrimentally affect the structure of neurons.

Memory formation begins at synapses, and it appears likely that destruction of memory formation is due to synapse failure. Our proposal investigates the molecular cause of this failure. It focuses on a new neurotoxin, called ADDLs, that was discovered and characterized by our group over the past several years. We previously showed that ADDLs accumulate in AD brains, so it is important to know how they act. Our most recent work established that ADDLs attack synapses, a fact that gives very strong support to the idea that AD is a synapse failure. We now want to discover what type of structural and molecular damage ADDLs cause to synapses after they bind. Our preliminary evidence strongly indicates that ADDLs rapidly change the geometry of synapses into a shape often seen in mental retardation. Our evidence also indicates that the neurotransmitter receptor molecules required for information storage are removed from synapses. We plan to verify and extend these preliminary results by new experiments using state-of-the-art experimental models to study synapse biology and the impact of ADDLs. Our experiments in the long run will determine how the ADDLs attack on synapses could result in the catastrophic memory failure suffered in early Alzheimer’s disease.