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: 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
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein E (apoE) is predominantly synthesized by astrocytes in the brain. In this study, we investigated the role of apoE in astrocyte apoptosis. We demonstrated that apoE protects astrocytes from hypoxia-induced apoptosis in a dose-dependent manner. Glutamate release from astrocytic cultures is significantly lower from WT mice than from apoE knockout mice. Furthermore, the protective effect of apoE is mimicked by an NMDA receptor antagonist, MK-801. Finally, the apoE activator T0901317 significantly reduced the effect of glutamate-induced apoptosis of astrocytes. These results suggest that apoE protects actrocytes from hypoxia-induced apoptosis associated to NMDA receptor activation. Approaches that elevate apoE secretion in astrocytes might provide a novel strategy in the protection of neuronal ischemic injury.
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