Terrone L. Rosenberry, Ph.D.

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SUMMARY

Terrone L. Rosenberry, Ph.D., is a neuroscience researcher who studies two components within the brain that may play a role in Alzheimer's disease. These components are amyloid-beta and acetylcholinesterase. Dr. Rosenberry works with research collaborators through his Protein Biochemistry and Neuroenzymology Laboratory.

Focus areas

• Amyloid beta. The brains of people with Alzheimer's disease contain large amounts of 40- and 42-residue amyloid-beta (Aβ) peptides that have aggregated to form fibrils in amyloid plaques. However, these peptides generate a variety of fibrils and smaller oligomers, some of which play important roles in the development of Alzheimer's disease. Dr. Rosenberry and his colleagues have produced a 150-kDa oligomer of the 42-residue form of Aβ. It is formed at a particular concentration of dilute anionic micelles that is slightly higher than their critical concentration. Researchers in Dr. Rosenberry's lab have obtained the oligomer's structure using solid-state nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM).

  In contrast to fibrils, which form β-sheets with parallel N- and C-strands, the 150-kDa oligomer has two β-strands simultaneously organized into both parallel and antiparallel β-sheets. Cryo-EM reconstruction reveals a four-fold symmetry and a central pore. Dr. Rosenberry and his collaborators are refining this structure to obtain a higher resolution and test the hypothesis that formation of the antiparallel C-strands occurs first in the assembly pathway by examining aggregation of Aβ(20-42). They're also investigating Aβ aggregates formed with other micelles to determine whether they, too, form oligomers.

• Acetylcholinesterase. Acetylcholinesterase (AChE) is an enzyme that controls communication between nerve cells by the neurotransmitter acetylcholine. This communication is disrupted by the death of nerve cells in people with Alzheimer's disease. Inhibitors of AChE are approved as medicines to elevate acetylcholine and aid neuronal function in Alzheimer's disease.

  AChE is also important in another context: It is inactivated by toxic agents such as organophosphates, and this can lead to neuromuscular paralysis and death. Certain pesticides and chemical warfare agents can expose people to organophosphates. Dr. Rosenberry and his collaborators are pursuing new therapeutic strategies to protect against organophosphate poisoning.

  The active site gorge of AChE contains two sites of ligand binding: an acylation site near the base of the gorge and a peripheral site at the mouth of the gorge some 1.5 to 2.0 nm from the acylation site. This peripheral site is an attractive target for the design of new medicines that might selectively protect against organophosphate reaction at the acylation site.

  Work in Dr. Rosenberry's lab has clarified the role of this site in AChE function. Lab researchers first showed that small ligands that bind selectively to the peripheral site inhibit AChE by slowing the rates at which substrates enter and exit the acylation site. They then found that substrates such as acetylthiocholine itself transiently bind to the peripheral site to accelerate their entry into the acylation site. Researchers also observed conformational interaction between the peripheral and the acylation sites. These studies led Dr. Rosenberry and his colleagues to embark on the design of new peripheral site ligands that may block the access of organophosphates but not acetylcholine to the acylation site, thereby offering protection against organophosphate toxicity.

Significance to patient care

Dr. Rosenberry's long-term research goal is determining which amyloid-beta structures form in the brain and what controls their assembly there. Preparing monoclonal antibodies to the antiparallel C-strand β-sheets may allow researchers to survey for these structures in vivo.

Dr. Rosenberry also hopes to determine whether the pore observed in the 150-kDa species has sufficient conductivity to provide toxic effects. His AChE work is directed toward selectively blocking irreversible organophosphate inhibition, an important goal in preventing large-scale nerve agent toxicity.