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

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 that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured as a greater-than-normal 1/ 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 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.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

Deuterium‐reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer's disease

“…Because of the variety of biochemical changes exhibited by Aldh2 À/À mice, and a lack of certainty as to the relative importance of these changes in mediating the observed cognitive deficits, we chose to use the changes in the behavioral responses as our index of efficacy of the D-PUFA-enriched diet. Of relevance to the improved cognitive performance exhibited by D-PUFAs is a recent study using quench-assisted MRI which demonstrated increased free radical production (and by extension increased LPO) in the dorsal CA1 region of the hippocampus of Aldh2 À/À mice relative to wild-type mice [65]. In rodents, this hippocampal subfield is associated with the encoding of spatial memory (which can be assessed by behavioral tests such as the MWM task), and is therefore consistent with the idea of a role for LPO in the impaired spatial reference memory exhibited by Aldh2 À/À mice, and further, its amelioration by D-PUFA treatment.…”

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

“…Amyloid β peptide (Aβ) deposition and neurofibrillary tangles in the AD hippocampus, which is the central brain region to exhibit neurodegeneration and other AD-related alterations, possibly lead to cognitive impairment [18,19]. In addition, hippocampal oxidative stress is implicated in neurodegenerative diseases and neurodevelopmental disorders [20,21]. However, no study has investigated the metabolomics profiling of the hippocampus in the 5xFAD mouse model.…”

Morphometric Analysis of Hippocampal and Neocortical Pyramidal Neurons in a Mouse Model of Late Onset Alzheimer’s Disease

“…Several lines of evidence suggest that the dorsal hippocampus is more vulnerable to damage by oxidative stress. Studies using quench-assisted MRI demonstrated increased free radical production in vivo in the dorsal but not intermediate CA1 region of the hippocampus of Aldh2 KO mice relative to wildtype mice [30], suggesting increased basal oxidative stress in this region. This same increase in free radical production was also observed in the dCA1 region in the 5XFAD mouse model of familial AD.…”