Glial changes are associated with cerebrovascular integrity in hyperhomocysteinemia‐induced VCID in mouse and human brain

Abstract

AbstractBackgroundWith the aged population estimated to double by 2050 and the rate of dementia expected to triple, it is critical to identify treatments for dementia. One of the leading causes of dementia is vascular contributions to cognitive impairment and dementia (VCID), and is frequently found co‐morbidly with Alzheimer’s disease, the other leading cause of dementia. A modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), which is defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), and most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy is a risk factor for VCID, the mechanism through which it induces cognitive impairment remains unclear.MethodWe used human and mouse brain tissue to determine glial and vascular changes associated with HHcy. Wild‐type (C57Bl6J) mice were placed on a HHcy or control diet for 6, 10, 14, or 18 weeks. Using qPCR, we investigated pro‐ and anti‐inflammatory cytokines. We also determined changes in microglia (IBA‐1) and identified the number of microhemorrhages and cognitive changes. In humans, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (<14µmol/L) and 18 had high plasma homocysteine levels (>14µmol/L). We determined whether the level of plasma homocysteine was associated with microglia (IBA‐1) and astrocytes (GFAP) as well as microhemorrhages and atherosclerosis severity in the frontal and occipital cortices. Both gene expression and protein inflammatory markers were measured to determine associations with plasma homocysteine.ResultIn our mouse model of HHcy, we identified a time course of glial changes that first begins with an increase in pro‐inflammatory cytokines and increases in microglial staining at 6 weeks on diet. This is followed by cognitive changes at 10 weeks on diet. Finally, at 14 weeks on diet, we see significant cognitive deficits due to HHcy. In human tissue, HHcy was associated with more microglia but fewer astrocytes, a significant decrease in inflammation and increased microhemorrhages in the frontal cortex.ConclusionTaken together, this data shows that in both mouse and human tissue, HHcy induces significant glial and vascular pathology that could be driven by inflammatory effects.