Mental HealthNew Mechanism For Amyloid Beta Protein's Toxic Impact On The Alzheimer's Brain
Scientists have uncovered a novel mechanism linking soluble amyloid í² protein with the synaptic injury and memory loss associated with Alzheimer"s disease (AD). The research, published by Cell Press 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 í² protein (Aí²) 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 Aí² 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 Aí² in the regulation of LTD has not been clearly described. The researchers found that soluble Aí² facilitated LTD in the hippocampus, a region of the brain intimately associated with memory. The enhanced synaptic depression induced by soluble Aí² 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 Aí²-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 Aí² directly and significantly decreased glutamate uptake by isolated synapses.
"Our findings provide evidence that soluble Aí² from several s 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 Aí² accumulation." Future studies are needed to determine precisely how soluble Aí² 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.
Cathleen Genova
Cell Press