2014-2015 Alzheimer’s and Related Diseases Research Award*

Analysis of Amyloid Beta Effects with Living Neuronal Networks

VCoA*The Virginia Center on Aging which administers the Alzheimer’s and Related Diseases Research Award Fund for the Commonwealth of Virginia, provides seed money to researchers in Virginia to stimulate innovative research into biomedical and psychosocial aspects of dementia, including cell biology, caregiving, and animal modeling.


Analysis of Amyloid Beta Effects with Living Neuronal Networks

Joseph J. Pancrazio, PhD

George Mason University

A hallmark feature of Alzheimer’s disease is the manifestation of amyloid plaques which are largely comprised of amyloid beta (Aβ). There are conflicting reports concerning the neurotoxicity of soluble Aβ oligomer, monomer, and fiber forms. In addition, various receptors have been identified that may mediate functional neurotoxicity or cytoxicity in neurons. The principal approach of this research group involves the use of cultured murine cortical neuronal networks on microelectrode arrays. This well established technique allows noninvasive, long-term measurement of physiologically relevant bioelectrical activity. They aim to: 1) compare the relative potency of the oligomer, monomer, and fiber forms of Aβ on spontaneous bioelectrical activity and cytotoxicity in neuronal networks; 2) determine the role of excitatory receptor modulation in Aβ neurotoxicity effects; and 3) examine the capacity of a custom peptide that binds Aβ to interfere with neurotoxicity effects. If successful, this work will lead to a new in vitro cell-based strategy for therapeutic screening.

(Dr. Pancrazio may be contacted at 703/993-1605, jpancraz@gmu.edu)

REPORT:

Assays based on dishes of cells offer a means of screening potential therapeutics and accelerating the drug development process. In this study, the investigator used dishes of interconnected brain cells or neurons on electrical recording devices called microelectrode arrays to examine the effects of amyloid-β 1-42 (Aβ42), a biomolecule implicated in the Alzheimer’s disease process. The research showed that a special form of Aβ, oligomeric but not the monomeric, diminishes electrical activity from the network of neurons on the microelectrode arrays. This observation is important because clinical and animal model results suggest that the neuroactive form of Aβ is the oligomer and so the assay method is sensitive to the pathologically relevant form of the molecule. The effects of the oligomer are persistent over a period of at least 24 hours and do not appear to be associated with cell death. In addition, the researcher demonstrated that the excitatory receptors in the brain, that are triggered by the neurotransmitter glutamate, play a role in the effects of Aβ42 on neuronal network activity. Exposure to blockers of these receptors modulated the time course of Aβ42 oligomer effects on the neuronal networks. Pretreatment of the neuronal networks with two model therapeutics, methylene blue and memantine, reversed the effects of oligomeric Aβ42. These findings suggest that cultured neuronal networks may be a useful platform in screening potential therapeutics for Aβ induced changes in neurological function.

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