Reduction of brain plasticity underlies the poor outcome of aged stroke patients. The molecular mechanism of plasticity reduction by aging is uncertain, but disturbed lipid metabolism may be implicated.
We investigated the expression of low density lipoprotein receptors (LDL-R) and apolipoprotein E (ApoE), both of which play active roles in lipid metabolism in young adult and old rat brains after ischemia.
LDL-R, trivially expressed in the sham-operated brain neurons, was increased from day 1 and became prominent at days 7 and 21 at the peri-ischemic cortex. The magnitude was smaller in the old than in the young adult rats. ApoE was increased in the astrocytes and neurons of the peri-ischemic cortex at day 1, which became further pronounced in the neurons but not in the astrocytes at days 7 and 21. ApoE expression was again less prominent in the old animals at days 7 and 21.
As ApoE-containing lipoprotein is recruited via LDL-R, the present results suggest that old brains had less capability to induce LDL-R, which resulted in impaired recruitment of lipoprotein after the ischemic injury. Impaired lipid recruitment causes disturbance of synaptogenesis and thus brain plasticity reduction. This molecular mechanism may result in poor functional recovery of aged stroke patients.
[Show abstract][Hide abstract] ABSTRACT: The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for late-onset AD is the presence of the epsilon4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-beta peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that a high cholesterol (HC) diet results in increases in microglia load and levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the brains of wild type (WT) and apolipoprotein E knockout (ApoE-/-) mice. In the present investigation, we analyzed whether treatment with rosuvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, would prevent the increases in inflammatory microglia and IL-6 levels in the brain and plasma of WT and ApoE-/- mice. We report that a HC diet resulted in an increased microglia load in the brains of WT and ApoE-/- mice, in support of our previous study. Treatment with rosuvastatin significantly decreased the microglia load in the brains of WT and ApoE-/- mice on a HC diet. Rosuvastatin treatment resulted in lowered plasma IL-6 levels in WT mice on a HC diet. However, in the present study the number of IL-6 positive cells in the brain was not significantly affected by a HC diet. A recent clinical study has shown that rosuvastatin reduces risk of ischemic stroke in patients with high plasma levels of the inflammatory marker C-reactive protein by 50%. The results from our study show that rosuvastatin reduces inflammatory cells in the brain. This finding is essential for furthering the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and stroke.
Biochemical and Biophysical Research Communications 10/2010; 402(2):367-72. DOI:10.1016/j.bbrc.2010.10.035 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Animal models of acute ischemic stroke have been criticized for failing to translate to human stroke. Nevertheless, animal models are necessary to improve our understanding of stroke pathophysiology and to guide the development of new stroke therapies. The rabbit embolic clot model is one animal model that has led to an effective therapy in human acute ischemic stroke, namely tissue plasminogen activator (tPA). We propose that potential compounds that demonstrate efficacy in non-rabbit animal models of acute ischemic stroke should also be tested in the rabbit embolic blood clot model and, where appropriate, compared to tPA prior to investigation in humans. Furthermore, the use of anesthesia needs to be considered as a major confounder in animal models of acute ischemic stroke, and death should be included as an outcome measure in animal stroke studies. These steps, along with the current STAIRs recommendations, may improve the successful translation of experimental therapies to clinical stroke treatments.
Translational Stroke Research 06/2011; 2(2):138-143. DOI:10.1007/s12975-011-0067-3 · 2.44 Impact Factor
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