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New Mechanism For Amyloid Beta Protein's Toxic Impact On The Alzheimer's Brain

Date:
July 6, 2009
Source:
Cell Press
Summary:
Scientists have uncovered a novel mechanism linking soluble amyloid b protein with the synaptic injury and memory loss associated with Alzheimer's disease (AD). The research provides critical new insight into disease pathogenesis and reveals signaling molecules that may serve as potential additional therapeutic targets for AD.

Scientists have uncovered a novel mechanism linking soluble amyloid ? protein with the synaptic injury and memory loss associated with Alzheimer's disease (AD). The research, published in the June 25 issue of the journal Neuron, provides critical new insight into disease pathogenesis and reveals signaling molecules that may serve as potential additional therapeutic targets for AD.

Amyloid ? protein (A?) plays a major pathogenic role in AD, a devastating neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. "Given the mounting evidence that small soluble A? assemblies mediate synaptic impairment in AD, 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 from the Center for Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School.

Dr. Selkoe, Dr. Shaomin Li, 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 A? in the regulation of LTD has not been clearly described. The researchers found that soluble A? facilitated LTD in the hippocampus, a region of the brain intimately associated with memory. The enhanced synaptic depression induced by soluble A? was mediated through a decrease in glutamate recycling at hippocampal synapses.

Excess glutamate, the major excitatory neurotransmitter in the brain, is thought to contribute to the progressive neuronal loss characteristic of AD. The researchers went on to show that A?-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 A? directly and significantly decreased glutamate uptake by isolated synapses.

"Our findings provide evidence that soluble A? 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 AD and in more subtle forms of age-related A? accumulation." Future studies are needed to determine precisely how soluble A? protein physically interferes with glutamate transporters at the synapse.

The researchers include Shaomin Li, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Soyon Hong, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Nina E. Shepardson, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Dominic M. Walsh, University College Dublin, Dublin, Ireland; Ganesh M. Shankar, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Dennis Selkoe, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Cite This Page:

Cell Press. "New Mechanism For Amyloid Beta Protein's Toxic Impact On The Alzheimer's Brain." ScienceDaily. ScienceDaily, 6 July 2009. <www.sciencedaily.com/releases/2009/06/090624153100.htm>.
Cell Press. (2009, July 6). New Mechanism For Amyloid Beta Protein's Toxic Impact On The Alzheimer's Brain. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2009/06/090624153100.htm
Cell Press. "New Mechanism For Amyloid Beta Protein's Toxic Impact On The Alzheimer's Brain." ScienceDaily. www.sciencedaily.com/releases/2009/06/090624153100.htm (accessed October 21, 2014).

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