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Abstract
AimsApoB-100 is the major protein component of cholesterol- and triglyceride-rich LDL and VLDL lipoproteins in the serum. Previously, we generated and partially described transgenic mice overexpressing the human ApoB-100 protein. Here, we further characterize this transgenic strain in order to reveal a possible link between hypeprlipidemia and neurodegeneration.Methods and ResultsWe analyzed the serum and cerebral lipid profiles, tau phosphorylation patterns, amyloid plaque-formation, neuronal apoptosis and synaptic plasticity of young (3 month old), adult (6 month old) and aging (10–11 month old) transgenic mice. We show that ApoB-100 transgenic animals present i) elevated serum and cerebral levels of triglycerides and ApoB-100, ii) increased cerebral tau phosphorylation at phosphosites Ser199, Ser199/202, Ser396 and Ser404. Furthermore, we demonstrate, that tau hyperphosphorylation is accompanied by impaired presynaptic function, long-term potentiation and widespread hippocampal neuronal apoptosis.ConclusionsThe results presented here indicate that elevated ApoB-100 level and the consequent chronic hypertriglyceridemia may lead to impaired neuronal function and neurodegeneration, possibly via hyperphosphorylation of tau protein. On account of their specific phenotype, ApoB-100 transgenic mice may be considered a versatile model of hyperlipidemia-induced age-related neurodegeneration.
Highlights
Over the last few years, increasing number of evidence has highlighted the relationship between hyperlipidemia-induced cerebrovascular disorders and age-related cognitive decline [1]
We demonstrate, that tau hyperphosphorylation is accompanied by impaired presynaptic function, long-term potentiation and widespread hippocampal neuronal apoptosis
The results presented here indicate that elevated ApoB-100 level and the consequent chronic hypertriglyceridemia may lead to impaired neuronal function and neurodegeneration, possibly via hyperphosphorylation of tau protein
Summary
Over the last few years, increasing number of evidence has highlighted the relationship between hyperlipidemia-induced cerebrovascular disorders and age-related cognitive decline [1]. Vascular dementia is a common cause of cognitive decline in the elderly and is associated with atherogenic dyslipidemia being related to low density lipoprotein (LDL) and carotid atherosclerosis [2]. Recent studies indicate that ApoB-100-induced hyperlipidemia and atherosclerosis are implicated in the pathogenesis of cardiovascular disease but may affect the cerebrovascular system [4] contribute to the development of neurodegenerative disorders [5]. Most of AD cases are sporadic, less than 5% of cases of Alzheimer’s disease (AD) can be traced to genetic causes, strengthening the hypothesis that lifestyle and nutrition-related factors may contribute to the development of metabolic syndrome and vascular lesions that eventually lead to neurodegenerative disorders [8]
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