Molecular Targets of Synaptic Dysfunction in AD

A significant amount of early memory deficit in Alzheimer’s disease (AD) is caused by abnormal communication between nerve cells in the hippocampus, a brain region dedicated to memory formation. Such communication occurs at excitatory synapses, specialized cell-cell contact sites where the neurotransmitter glutamate is released and detected. A prominent form of AD-associated synapse dysfunction is the impairment of synaptic plasticity by beta-amyloid (Aß), the protein fragment that accumulates in the brains of Alzheimer’s patients. A newly recognized mechanism for changing synaptic strength is the removal of neurotransmitter receptors that detect the neurotransmitter glutamate by a process called endocytosis. Dr. Ehlers has found that Aß peptides cause a selective activation of endocytosis molecules with a simultaneous loss of glutamate receptors at hippocampal synapses. Using his preliminary data, Dr. Ehlers is working to define the underlying cellular mechanism of the Aß-dependent disturbance of endocytosis and to identify molecular signals that restore normal synapse function in the amyloid-exposed brain.