Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue

Abstract

Introduction Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. Methods A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium‐binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L). Results Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S‐adenosyl‐homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Conclusions Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

Atorvastatin rescues hyperhomocysteinemia-induced cognitive deficits and neuroinflammatory gene changes

“…The majority of gene changes with a significant P value occurred between control and HHcy mice (35 genes) and between HHcy and HHcy with atorvastatin mice (108 genes). Interestingly, the HHcy diet caused reduced gene expression of every significant gene, similar to what we have previously reported in human brain tissue with HHcy, while atorvastatin increased gene expression [ 35 ]. A possible explanation for this could be due to the SAM/SAH ratio and the restored DNA methylation potential.…”

Homocysteine potentiates amyloid β‐induced death receptor 4‐ and 5‐mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment

“…Previous studies demonstrated that Hhcy accelerates cerebral amyloidosis and CAA, exacerbating deficits in CBF and cerebrovascular dysfunction in AD mouse models (Braun et al., 2019 ; Li et al., 2014 ; Li & Pratico, 2015 ; Sudduth et al., 2013 ; Zhuo et al., 2010 ; Zhuo & Pratico, 2010 ). Additionally, neuroinflammatory processes, microhemorrhages and cerebrovascular atherosclerosis were observed in postmortem human brains of patients with Hhcy (Weekman et al., 2022 ). It is evident that Hhcy has severe pathological consequences on the cerebrovascular environment.…”

Homocysteine and Parkinson's disease

“…And it was found that the expression of genes associated with inflammation in astrocytes and microglia was significantly changed after Hcy treatment 70 . In addition, other studies found that the immune reactivity of the astrocyte marker GFAP and the microglia marker IBA1 in the brain tissues of HHcy patients was significantly enhanced compared with those of healthy controls 71 …”

“… 70 In addition, other studies found that the immune reactivity of the astrocyte marker GFAP and the microglia marker IBA1 in the brain tissues of HHcy patients was significantly enhanced compared with those of healthy controls. 71 …”