Alterations in Brain Cholesterol Metabolism in the APPSLxPS1mut mouse, a Model for Alzheimer's Disease

2010 ◽  
Vol 19 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Tim Vanmierlo ◽  
Vincent W. Bloks ◽  
Leonie C. van Vark-van der Zee ◽  
Kris Rutten ◽  
Anja Kerksiek ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Brain Cholesterol

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

2009 ◽  
Vol 24 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Heike Kölsch ◽  
Dieter Lütjohann ◽  
Frank Jessen ◽  
Julius Popp ◽  
Frank Hentschel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Cholesterol Metabolism ◽  
Disease Risk ◽  
Brain Cholesterol ◽  
Increased Risk ◽  
Csf Levels ◽  
Interaction Term ◽  
Gene Variability

AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

The conflicting role of brain cholesterol in Alzheimer's disease: lessons from the brain plasminogen system.

2005 ◽  
Vol 72 ◽  
pp. 129-138 ◽  
Author(s):  
Maria Dolores Ledesma ◽  
Carlos G. Dotti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Synthesis ◽  
Cultured Cells ◽  
Cholesterol Metabolism ◽  
Amyloid Peptide ◽  
High Brain ◽  
Brain Cholesterol ◽  
Ad Alzheimer’S Disease ◽  
Abeta Production

Retrospective clinical studies indicate that individuals chronically treated with cholesterol synthesis inhibitors, statins, are at lower risk of developing AD (Alzheimer's disease). Moreover, treatment of guinea pigs with high doses of simvastatin or drastic reduction of cholesterol in cultured cells decrease Aβ (β-amyloid peptide) production. These data sustain the concept that high brain cholesterol is responsible for Aβ accumulation in AD, providing the scientific support for the proposed use of statins to prevent this disease. However, a number of unresolved issues raise doubts that high brain cholesterol is to blame. First, it has not been shown that higher neuronal cholesterol increases Abeta production. Secondly, it has not been demonstrated that neurons in AD have more cholesterol than control neurons. On the contrary, the brains of AD patients show a specific down-regulation of seladin-1, a protein involved in cholesterol synthesis, and low membrane cholesterol was observed in hippocampal membranes of ApoE4 (apolipoprotein E4) AD cases. This effect was also evidenced by altered cholesterol-rich membrane domains (rafts) and raft-mediated functions, such as diminished generation of the Aβ-degrading enzyme plasmin. Thirdly, numerous genetic defects that cause neurodegeneration are due to defective cholesterol metabolism. Fourthly, in female mice, the most brain-permeant statin induces neurodegeneration and high amyloid production. Altogether, this evidence makes it difficult to accept that statins are beneficial through acting as brain cholesterol-synthesis inhibitors. It appears more likely that their advantageous role arises from improved brain oxygenation.

P2-153: Alterations of brain cholesterol metabolism: Relevance of desmosterol in Alzheimer's disease and vascular dementia

2006 ◽  
Vol 2 ◽  
pp. S278-S278
Author(s):  
Heike Kölsch ◽  
Reinhard Heun ◽  
Frank Jessen ◽  
Julius Popp ◽  
Wolfgang Maier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Cholesterol Metabolism ◽  
Brain Cholesterol

scholarly journals Oxysterols Present in Alzheimer’s Disease Braininduce Synaptoxicity by Activating Astrocytes: A Major Role for Lipocalin-2

2020 ◽  
Author(s):  
Erica Staurenghi ◽  
Valentina Cerrato ◽  
Paola Gamba ◽  
Gabriella Testa ◽  
Serena Giannelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Reactive Astrocytes ◽  
Cholesterol Oxidation ◽  
Neuronal Cultures ◽  
Lipocalin 2 ◽  
Brain Cholesterol ◽  
The Impact

Abstract Background: Among Alzheimer’s disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis.In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health.Methods: Mouse primary astrocyte cultures were used to test the effect of two oxysterol mixtures, that represent the oxysterol composition respectively of mild or severe AD brains, on astrocyte morphology, markers of reactivity, and secretion profile. Co-culture experiments were performed to investigate the impact of oxysterol-treated astrocytes on neurons. Neuronal cultures were exposed to astrocyte conditioned media (ACM) deprived of lipocalin-2 (Lcn2) to investigate the contribution of this mediator to synaptotoxicity.Results: Results showed that oxysterols induce a clear morphological change in astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including Lcn2. Moreover, ACM analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. Conclusions: These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.

scholarly journals The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 740
Author(s):  
Paola Gamba ◽  
Serena Giannelli ◽  
Erica Staurenghi ◽  
Gabriella Testa ◽  
Barbara Sottero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Cholesterol Homeostasis ◽  
Oxidation Products ◽  
Cholesterol Oxidation ◽  
Brain Cholesterol ◽  
The Brain

The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression.

Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment

2010 ◽  
Vol 38 (4) ◽  
pp. 1021-1025 ◽  
Author(s):  
Valerio Leoni ◽  
Alina Solomon ◽  
Miia Kivipelto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
Brain Cholesterol ◽  
Neurodegenerative Process ◽  
Signalling Molecule

Brain neurons remove the excess of cholesterol via conversion into the more polar 24OHC [(24S)-hydroxycholesterol]. 24OHC acts as a signalling molecule inducing ApoE (apolipoprotein E)-mediated cholesterol efflux from astrocytes, by a direct effect on ApoE transcription, protein synthesis and secretion. In CSF (cerebrospinal fluid) collected form from patients with cognitive impairment (Alzheimer's disease and patients with mild cognitive impairment) the levels of ApoE, tau, p-tau (hyperphosphorylated tau) were significantly increased, together with 24OHC, compared with controls. We also found that the levels of tau and p-tau were significantly correlated with ApoE and 24OHC in the same samples. Such a correlation was not found in control patients. Increased levels of cholesterol in membranes and impairment in brain cholesterol metabolism were found to be involved both in APP (amyloid precursor protein) processing and amyloid β-peptide deposition and, recently, in tau pathology. The CSF tau levels are considered to be related to the neurodegenerative process in Alzheimer's disease. During neurodegeneration, the cholesterol accumulated in neurons is converted into 24OHC. The release of 24OHC from neurons induces ApoE secretion by astrocytes, and both are related to the intensity of the neurodegenerative process and neuronal injury. ApoE can also be involved in the scavenging of tau from neurons. The direct correlations between ApoE, 24OHC and tau suggest that cholesterol metabolism may be involved in generation of both tau and amyloid β-peptide and that the ApoE is released by astrocytes in order to counteract this ongoing process.

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