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2012 Grants - Grabrucker
Investigating the Physiological Role of Zinc Binding to Beta-Amyloid
Andreas M. Grabrucker, Ph.D.
University Hospital Ulm
2012 New Investigator Research Grant
The protein fragment beta-amyloid tends to accumulate in the brains of people with Alzheimer's disease, eventually forming clump-like plaques that are a hallmark of the disease. Recent studies, however, have found that smaller beta-amyloid aggregates, which occur in the early stages of amyloid deposition, are more toxic to the brain than plaques. These small aggregates are known as oligomers, and they have been shown to damage cell-to-cell communication in the brain and cause dementia-related memory loss. Though the exact mechanisms by which oligomers exert their toxicity are unknown, current evidence has found that metal ions (or electrically charged metal particles) may play a role in oligomer formation. When zinc and copper ions bind to individual beta-amyloid molecules, these molecules tend to begin aggregating.
In preliminary studies, Andreas M. Grabrucker, Ph.D., and colleagues have found that the binding of zinc and beta-amyloid negatively affects a protein called SHANK3. This protein helps form synapses, the tiny channels through which brain cells communicate with one another. For SHANK3 to function properly, it has to interact with zinc ions. But the binding of zinc to beta-amyloid makes these ions unavailable, causing SHANK3 activity to decrease. This process may help explain how amyloid oligomers are toxic to synapses. Dr. Grabrucker's team also noted that zinc can bind to the parent molecule of beta-amyloid—amyloid precursor protein (APP). Such binding appears to occur in healthy brains, and it may play a positive role in the growth of brain cells.
For their current study, Dr. Grabrucker and colleagues will assess how zinc/APP binding affects APP function in laboratory cells and in mice genetically engineered to develop Alzheimer's-like symptoms. They will also examine how the levels of zinc in the brain may influence zinc/APP interactions, and whether altered zinc levels may be associated with the production of harmful beta-amyloid. Results of this work could identify zinc as a prime target for new Alzheimer's therapies.