In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Bruce A. Berkowitz, Jacob Lenning, Nikita Khetarpal, Catherine Tran, Johnny Y. Wu, Ali M. Berri, Kristin Dernay, E. Mark Haacke, Fatema Shafie-Khorassani, Robert H. Podolsky, John C. Gant, Shaniya Maimaiti, Olivier Thibault, Geoffrey G. Murphy, Brian M. Bennett, Robin Roberts

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal–ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.

Original languageEnglish
Pages (from-to)4179-4186
Number of pages8
JournalFASEB Journal
Volume31
Issue number9
DOIs
StatePublished - Sep 2017

Bibliographical note

Funding Information:
This work was supported, in part, by the U.S. National Institutes of Health (NIH)/National Eye Institute (NEI) (Grants R21EY021619 and R01EY026584 to B.A.B.), NIH/National Institute on Aging (Grants R01 AG033649 to O.T. and R01 AG028488 to G.G.M.), Alzheimer’s Society Research Program (B.M.B.), the Canadian Vascular Network (B.M.B.), University of Michigan Protein Folding Disease Initiative (G.G.M.), NIH/ NEI Core Grant P30 EY04068, and an unrestricted grant from Research to Prevent Blindness (Kresge Eye Institute, Detroit, MI, USA).

Publisher Copyright:
© FASEB.

Keywords

  • Dorsoventral CA1
  • MRI
  • Neurodegenerative disease
  • Neurodevelopment disorders
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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