Association of Induced Hyperhomocysteinemia with Alzheimer’s Disease-Like Neurodegeneration in Rat Cortical Neurons After Global Ischemia-Reperfusion Injury

Abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that results in massive hippocampal and neocortical neuronal loss leading to dementia and eventual death. The exact cause of Alzheimer's disease is not fully explored, although a number of risk factors have been recognized, including high plasma concentration of homocysteine (Hcy). Hyperhomocysteinemia (hHcy) is considered a strong, independent risk factor for stroke and dementia. However, the molecular background underlying these mechanisms linked with hHcy and ischemic stroke is not fully understood. Paper describes rat model of global forebrain ischemia combined with the experimentally induced hHcy. Global ischemia-reperfusion injury (IRI) was developed by 4-vessels occlusion lasting for 15 min followed by reperfusion period of 72 h. hHcy was induced by subcutaneous injection of 0.45 µmol/g of Hcy in duration of 14 days. The results showed remarkable neural cell death induced by hHcy in the brain cortex and neurodegeneration is further aggravated by global IRI. We demonstrated degeneration of cortical neurons, alterations in number and morphology of tissue astrocytes and dysregulation of oxidative balance with increased membrane protein oxidation. Complementary to, an immunohistochemical analysis of tau protein and β-amyloid peptide showed that combination of hHcy with the IRI might lead to the progression of AD-like pathological features. Conclusively, these findings suggest that combination of risk factor hHcy with IRI aggravates neurodegeneration processes and leads to development of AD-like pathology in cerebral cortex.

Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus

“…It suggests that the dose and duration of Met intake (2 g/kg within 28 days) is not linked with the clearly visible signs of neuronal disintegration in the CA1 hippocampal region. On the other hand, hHcy induced by subcutaneous administration of Hcy for 14 days was manifested by remarkable disintegration of neuronal tissues detected by FluoroJade staining in the cerebral cortex and hippocampus [10,11]. This indicates the diverse effect of hHcy induction, which is probably linked with the direct toxic impact of Hcy or its metabolites.…”

“…Our previous works documented that subcutaneous administration of Hcy in rats led to the development of mild hHcy [10][11][12]. This hHcy condition resulted in the disintegration of neuronal tissue in the cerebral cortex as well as the hippocampus.…”

Proteomic and Genomic Changes in Tau Protein, Which Are Associated with Alzheimer’s Disease after Ischemia-Reperfusion Brain Injury

“…Tau protein accumulated in the blood after a ischemia-reperfusion brain episode [78,79] can cross the ischemic blood-brain barrier and tau protein originating from serum can cause a stronger tau protein pathology in the brain parenchyma [80]. Ischemia-reperfusion brain injury with ischemic insufficiency of the blood-brain barrier [7,[81][82][83][84][85] initiates tau protein phosphorylation [53,54,56,57,77], and phosphorylated tau protein may cause damage to the blood-brain barrier, leading to harmful feedback reactions [74]. The permeability of the blood-brain barrier may exacerbate neuropathology through the tau protein from blood in brain damage as a result of ischemia-reperfusion by increasing its level in brain tissue, which suggests that the ischemic-reperfusion episode of the brain may play an important role in the growth of the blood tau protein level [78][79][80].…”

“…The formation of neurofibrillary tangles was observed after focal ischemia-reperfusion injury of the brain on the side of massive cerebral infarction in humans (Table 1) [54]. In addition, the combination of total brain ischemia with hyperhomocysteinemia in rats led to enormous neuronal changes in the hippocampus and cortex caused by hyperphosphorylated tau protein (Table 1) [56]. The above study reported a 695-fold increase in hyperphosphorylated tau protein-positive neurons in the ischemic brain compared to the control [56].…”

Neuroprotective Effects of Choline and Other Methyl Donors

“…Choline supplementation in a mouse model of AD ameliorated cognitive functions in the first and second generations of mice and reduced the levels of homocysteine in their brain. Elevated levels of homocysteine have been linked to increased risk of AD development [102]. These observed changes in the AD mouse model in response to choline supplementation correlated with alteration in the expression of key genes related to inflammation, histone marks changes and neuronal death [100].…”