1. 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
- Author
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David J. Braun, David K. Powell, Christopher J. McLouth, Saktimayee M. Roy, D. Martin Watterson, and Linda J. Van Eldik
- Subjects
Physiology ,Anti-Inflammatory Agents ,Social Sciences ,Alzheimer's Disease ,Hippocampus ,Diagnostic Radiology ,Mice ,Medical Conditions ,Immune Physiology ,Medicine and Health Sciences ,Psychology ,Mammals ,Innate Immune System ,Multidisciplinary ,Behavior, Animal ,Animal Behavior ,Radiology and Imaging ,Brain ,Eukaryota ,Neurodegenerative Diseases ,Animal Models ,Magnetic Resonance Imaging ,Neurology ,Experimental Organism Systems ,Vertebrates ,Cytokines ,Medicine ,Anatomy ,Research Article ,Imaging Techniques ,Science ,Immunology ,Mouse Models ,Research and Analysis Methods ,Rodents ,Model Organisms ,Memory ,Diagnostic Medicine ,Mental Health and Psychiatry ,mental disorders ,Animals ,Maze Learning ,Nutrition ,Memory Disorders ,Behavior ,Organisms ,Biology and Life Sciences ,Collective Animal Behavior ,Molecular Development ,Diet ,Disease Models, Animal ,Immune System ,Amniotes ,Animal Studies ,Dementia ,Zoology ,Developmental Biology - 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.
- Published
- 2022