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2005 Grant - Holtzman

Effects of Neurotransmitters and Synaptic Activity on Brain ISF Beta-Amyloid

David M. Holtzman, M.D.
Washington University
St. Louis, Missouri

2005 Zenith Fellows Award

In the Alzheimer's disease brain, beta-amyloid protein fragments aggregate, or clump together, outside cells. A large body of evidence suggests that some aggregated forms of beta-amyloid have a toxic effect that disrupts cell-to-cell communication and damages cells. Recent studies have also shown that neurons may normally produce and release beta-amyloid and that levels of beta-amyloid accumulation are moderated by neural activity, or how frequently nerve cells communicate with each other.

David Holtzman, M.D., and colleagues have developed a method to assess the levels of beta-amyloid in interstitial fluid (ISF), the fluid surrounding brain cells, in living, awake mice. These genetically altered mice carry a human Alzheimer-related gene and develop beta-amyloid aggregations.

In order to determine whether and how neural activity controls beta-amyloid levels in the brain, the researchers will use drugs and electrical stimulation to decrease or increase neural activity and monitor subsequent alterations in beta-amyloid concentrations. They will also examine whether artificial regulation of the brain's chemical messengers induces a similar change in amyloid concentrations. This work may clarify unknown factors about beta-amyloid pathology and suggest new lines of investigation for therapies.