Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events

• Published in: Journal of neuroinflammation Vol. 16; no. 1; pp. 284 - 11
• Main Authors: Weekman, Erica M, Sudduth, Tiffany L, Price, Brittani R, Woolums, Abigail E, Hawthorne, Danielle, Seaks, Charles E, Wilcock, Donna M
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30-12-2019; BioMed Central; BMC
• Subjects: Advertising executives; Alzheimer's disease; Amyloid - metabolism; Analysis; Animal cognition; Animals; Astrocytic end-feet; Brain - metabolism; Brain - pathology; Cerebrovascular Disorders - metabolism; Cerebrovascular Disorders - pathology; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Creutzfeldt-Jakob disease; Dementia; Dementia disorders; Diet; Disease Models, Animal; Female; Folic acid; Gene expression; Genes; Genetic research; Homocysteine; Humans; Hyperhomocysteinemia; Hyperhomocysteinemia - complications; Immunohistochemistry; Inflammation; Inflammation - metabolism; Inflammation - pathology; Interleukin 1; Interleukin 6; Interleukins; Laboratory animals; Magnetic resonance imaging; Male; Methionine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microhemorrhage; Microscopy; Morbidity; Mutation; Necrosis; Neurodegenerative diseases; Neuroinflammation; Neuropathology; Nutrient deficiency; Parenchyma; Pathology; Phenotypes; Physiological aspects; Plaque, Amyloid - pathology; Presenilin 1; Proteins; Stroke; Therapeutic applications; Time Factors; Transcriptome; Tumor necrosis factor-α; Tumors; Vascular contributions to cognitive impairment and dementia; Vitamin B; Vitamin B12; Vitamin B6; Vitamins; United States > US; Indianapolis Indiana; Neuroinflammation; Hyperhomocysteinemia; Microhemorrhage; Vascular contributions to cognitive impairment and dementia; Alzheimer’s disease; Astrocytic end-feet
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-019-1685-z

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer's disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice.
APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze.
Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature.
The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.