Researchers have uncovered a novel mechanism linking soluble amyloid β protein with the synaptic injury and memory loss associated with Alzheimer's disease. The research provides critical new insight into the development of Alzheimer's and reveals signaling molecules that may serve as potential additional therapeutic targets for Alzheimer's.

Alzheimer’s is a disease of the brain that destroys brain cells, causing problems with memory, thinking and behavior. In 2009, it is estimated that there are as many as 5.3 million Americans living with Alzheimer’s. By 2010, there will be nearly a half million new cases of Alzheimer’s each year and by 2050, there will be nearly a million new cases of Alzheimer’s annually.

Amyloid β protein (Aβ) plays a major role in the development of Alzheimer's, a devastating neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. "Given the mounting evidence that small soluble Aβ assemblies mediate synaptic impairment in Alzheimer's, elucidating the precise molecular pathways by which this occurs has important implications for treating and preventing the disease," explains senior study author, Dr. Dennis Selkoe.

Dr. Selkoe and colleagues examined regulation of a cellular communication phenomenon known as long-term synaptic depression (LTD). LTD has been linked with neuronal degeneration, but a role for Aβ in the regulation of LTD has not been clearly described. The researchers found that soluble Aβ facilitated LTD in the hippocampus, a region of the brain intimately associated with memory. The enhanced synaptic depression induced by soluble Aβ was mediated through a decrease in glutamate recycling at hippocampal synapses (connections between neurons).

Excess glutamate, the major excitatory neurotransmitter in the brain, is thought to contribute to the progressive neuronal loss characteristic of Alzheimer's. The researchers went on to show that Aβ-enhanced LTD was mediated by glutamate receptor activity and that the LTD could be prevented by an extracellular glutamate scavenger system. A very similar enhancement of LTD could be induced by a pharmacological blocker of glutamate reuptake. Importantly, soluble Aβ directly and significantly decreased glutamate uptake by isolated synapses.

"Our findings provide evidence that soluble Aβ from several sources enhances synaptic depression through a novel mechanism involving altered glutamate uptake at hippocampal synapses," concludes Dr. Selkoe. "These results have both mechanistic and therapeutic implications for the initiation of hippocampal synaptic failure in Alzheimer's and in more subtle forms of age-related Aβ accumulation." Future studies are needed to determine precisely how soluble Aβ protein physically interferes with glutamate transporters at the synapse.

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References:
1. Dr. Dennis Selkoe, et al. Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake. Neuron, Volume 62, Issue 6, 788-801, 25 June 2009. doi:10.1016/j.neuron.2009.05.012

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