Therapeutic Treatment with the Anti-Inflammatory Drug Candidate MW151 May Partially Reduce Memory Impairment and Normalizes Hippocampal Metabolic Markers in a Mouse Model of Comorbid Amyloid and Vascular Pathology

Authors

David J. Braun, University of KentuckyFollow
David K. Powell, University of KentuckyFollow
Christopher J. McLouth, University of KentuckyFollow
Saktimayee M. Roy, Northwestern University
D. Martin Watterson, Northwestern University
Linda J. Van Eldik, University of KentuckyFollow

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop small molecule, anti-inflammatory therapeutics for neurological injury and disease, we have recently been exploring potentially promising treatments in preclinical multi-morbidity contexts. In the present study, we generated a mouse model of mixed amyloid and hyperhomocysteinemia (HHcy) pathology in which to test the efficacy of one of our anti-inflammatory compounds, MW151. HHcy can cause cerebrovascular damage and is an independent risk factor for both AD dementia and vascular contributions to cognitive impairment and dementia. We found that MW151 was able to partially rescue hippocampal-dependent spatial memory and learning deficits in this comorbidity context, and further, that the benefit is associated with a normalization of hippocampal metabolites detectable via magnetic resonance spectroscopy. These findings provide evidence that MW151 in particular, and potentially anti-inflammatory treatment more generally, may be beneficial in AD patients with comorbid vascular pathology.

Document Type

Article

Publication Date

1-26-2022

Notes/Citation Information

Published in PLOS ONE, v. 17, 0262474.

© 2022 Braun et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pone.0262474

Funding Information

This work was supported by a National Institute on Aging (NIA) Fellowship F32AG058456 (DJB), RF1AG064859 (LVE), and R01AG061898 (LVE, DMW).

Repository Citation

Braun, David J.; Powell, David K.; McLouth, Christopher J.; Roy, Saktimayee M.; Watterson, D. Martin; and Van Eldik, Linda J., "Therapeutic Treatment with the Anti-Inflammatory Drug Candidate MW151 May Partially Reduce Memory Impairment and Normalizes Hippocampal Metabolic Markers in a Mouse Model of Comorbid Amyloid and Vascular Pathology" (2022). Neuroscience Faculty Publications. 81.
https://uknowledge.uky.edu/neurobio_facpub/81