Essential role for cholesterol in synaptic plasticity and neuronal degeneration

Koudinov, Alexei R.; Koudinova, Natalia V.

doi:10.1096/fj.00-0815fje

Cited by 263 publications

(252 citation statements)

References 77 publications

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“…Cholesterol is an essential molecule for many other physiologic processes as well. Cholesterol plays an important role in the transformation or transportation of steroid hormones (estrogens, androgens) and lipid-soluble vitamin and delivery of lipid-soluble vitamin to cells, which are essential for basic synaptic integrity and neurotransmission (41)(42)(43). The observed positive association between cholesterol level and cognitive function is also consistent with recent studies showing that cholesterol depletion may increase the risk of blood-brain barrier breakdown, with resulting progressive synaptic and neuronal dysfunction and cognitive impairment (44).…”

Section: Discussionsupporting

confidence: 81%

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Serum cholesterol levels within the high normal range are associated with better cognitive performance among Chinese elderly

Yin

Chei

et al. 2016

The Journal of nutrition, health and aging

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Objectives-The association between cognitive function and cholesterol levels is poorly understood and inconsistent results exist among the elderly. The purpose of this study is to investigate the association of cholesterol level with cognitive performance among Chinese elderly.Design-A cross-sectional study was implemented in 2012 and data were analyzed using generalized additive models, linear regression models and logistic regression models. Conflict of interestThe authors declare that there are no conflicts of interests. Ethical standardsThe authors declare that all the experiments of this study complied with the current laws of China in which they were performed. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptSetting-Community-based setting in eight longevity areas in China.Subjects-A total of 2000 elderly aged 65 years and over (mean 85.8±12.0 years) participated in this study. Measurements-Total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) concentration were determined and cognitive impairment was defined as Mini-Mental State Examination (MMSE) score≤23.Results-There was a significant positive linear association between TC, TG, LDL-C, HDL-C and MMSE score in linear regression models. Each 1 mmol/L increase in TC, TG, LDL-C and HDL-C corresponded to a decreased risk of cognitive impairment in logistic regression models. Compared with the lowest tertile, the highest tertile of TC, LDL-C and HDL-C had a lower risk of cognitive impairment. The adjusted odds ratios and 95% CI were 0.73(0.62-0.84) for TC, 0.81(0.70-0.94) for LDL-C and 0.81(0.70-0.94) for HDL-C. There was no gender difference in the protective effects of high TC and LDL-C levels on cognitive impairment. However, for high HDL-C levels the effect was only observed in women. High TC, LDL-C and HDL-C levels were associated with lower risk of cognitive impairment in the oldest old (aged 80 and older), but not in the younger elderly (aged 65 to 79 years).Conclusions-These findings suggest that cholesterol levels within the high normal range are associated with better cognitive performance in Chinese elderly, specifically in the oldest old. With further validation, low cholesterol may serve a clinical indicator of risk for cognitive impairment in the elderly.

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Section: Discussionsupporting

confidence: 81%

“…Interestingly, a deficiency in cellular cholesterol or a deficiency in cholesterol supply to neurons was shown to inhibit dendrite outgrowth (37) and synaptogenesis (38), and to induce neurodegeneration (26,39). Cholesterol may also be a limiting factor for synaptogenesis in the central nervous system (40).…”

Section: Discussionmentioning

confidence: 99%

Serum cholesterol levels within the high normal range are associated with better cognitive performance among Chinese elderly

Yin

Chei

et al. 2016

The Journal of nutrition, health and aging

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“…39 The SREBP-mediated stimulation of the cholesterol and fatty acid biosynthesis in glial cells may represent a novel and clinically relevant action of antipsychotic drugs, due to the important role of cholesterol in myelination and synaptogenesis. 15,18,19 There is accumulating evidence for white matter changes in the brain of schizophrenic patients (reviewed in Davis et al 21 ), and a meta-analysis revealed a small decrease in the whole brain white matter volume. 5 Regional white matter changes in the prefrontal cortex seem to be associated with the presence of negative symptoms in the patients.…”

Section: Antipsychotic-induced Lipogenesis In Glioma Cellsmentioning

confidence: 99%

“…16,17 Glial cells serve an important role in the supply of adequate amounts of cholesterol. In addition to its close link to the myelination process, gliaderived cholesterol has recently been demonstrated as essential for synaptogenesis, [18][19][20] acting as a glial growth factor. These data point at lipogenesis and myelin synthesis as interesting etiological candidate targets in schizophrenia, especially in light of the proposed neurodevelopmental disturbances in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

et al. 2005

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Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics. 2 Heritability has been demonstrated to play an important role in the etiology, but numerous genetic linkage and association studies have yielded conflicting results, although there are now several promising candidate susceptibility genes. 3 Brain imaging studies of schizophrenic patients have shown various structural and functional abnormalities, including enlargement of the ventricles and volume reductions in specific brain regions, 4,5 even in first episode and drug-naïve subjects. [6][7][8] On the other hand, degenerative histopathological findings are strikingly absent. These observations hint at a neurodevelopmental origin of the disorder (for a review, see Harrison and Lewis 9 and Liddle and Pantelis 10 ).

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“…In addition, cholesterol supplied as glial lipoproteins stimulates the axon outgrowth of central nervous system neurons (8,9). Moreover, previous studies have shown that glia-derived cholesterol is essential for synaptogenesis and synaptic plasticity (10,11). These lines of evidence suggest that membrane lipids play essential roles in neurite outgrowth and the formation of synapse neuronal polarity.…”

mentioning

confidence: 95%

Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

Zou

Minagawa

et al. 2005

Journal of Biological Chemistry

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The acquisition of neuronal type-specific morphogenesis is a central feature of neuronal differentiation and has important consequences for region-specific nervous system functions. Here, we report that the cell type-specific cholesterol profile determines the differential modulation of axon and dendrite outgrowths in hippocampal and cerebral cortical neurons in culture. The extent of axon and dendrite outgrowths is greater and the polarity formation occurs earlier in cortical neurons than in hippocampal neurons. The cholesterol concentrations in total homogenate and the lipid rafts from hippocampal neurons are significantly higher than those from cortical neurons. Cholesterol depletion by ␤-cyclodextrin markedly enhanced the neurite outgrowth and accelerated the establishment of neuronal polarity in hippocampal neurons, which were similarly observed in nontreated cortical neurons, whereas cholesterol loading had no effects. In contrast, both depletion and loading of cholesterol decreased the neurite outgrowths in cortical neurons. The stimulation of neurite outgrowth and polarity formation induced by cholesterol depletion was accompanied by an enhanced localization of Fyn, a Src kinase, in the lipid rafts of hippocampal neurons. A concomitant treatment with ␤-cyclodextrin and a Src family kinase inhibitor, PP2, specifically blocked axon outgrowth but not dendrite outgrowth (both of which were enhanced by ␤-cyclodextrin) in hippocampal neurons, suggesting that axon outgrowth modulated by cholesterol is induced in a Fyn-dependent manner. These results suggest that cellular cholesterol modulates axon and dendrite outgrowths and neuronal polarization under culture conditions and also that the difference in cholesterol profile between hippocampal and cortical neurons underlies the difference in neurite outgrowth between these two types of neurons.Neurons contain two types of processes, axons and dendrites, which are structurally and functionally distinct and play different roles in the maintenance of brain functions. There are studies showing the significant role of lipids in the formation of neuronal polarity; it has been shown that phospholipids regulate neurite outgrowth in cultured neurons (1) and that the correct distribution of axonal membrane proteins requires the formation of sphingomyelin/cholesterol-rich microdomains, lipid rafts, and the maturation of the axonal plasma membrane requires the up-regulation of sphingomyelin synthesis (2, 3). Cholesterol also plays a prominent role in raft-mediated trafficking and sorting, because cholesterol depletion by methyl-␤-cyclodextrin impedes trafficking from the trans-Golgi network to the apical membrane (4). It has been shown that cholesterol modulates dendrite outgrowth (5), that its deficiency enhances phosphorylation of tau and axonal depolymerization (6), and that axonal regeneration is dependent on local cholesterol reutilization in vivo (7). In addition, cholesterol supplied as glial lipoproteins stimulates the axon outgrowth of central nervous system neurons...

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Essential role for cholesterol in synaptic plasticity and neuronal degeneration

Cited by 263 publications

References 77 publications

Serum cholesterol levels within the high normal range are associated with better cognitive performance among Chinese elderly

Serum cholesterol levels within the high normal range are associated with better cognitive performance among Chinese elderly

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

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