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

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.

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

Antioxidants ◽

10.3390/antiox10050740 ◽

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.

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

10.21203/rs.3.rs-52307/v1 ◽

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.

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Role of ABC transporters in the pathology of Alzheimer’s disease

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0060 ◽

2017 ◽

Vol 28 (2) ◽

pp. 155-159 ◽

Cited By ~ 6

Author(s):

Yan Zhao ◽

Deren Hou ◽

Xialu Feng ◽

Fangbo Lin ◽

Jing Luo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Present Article ◽

Abc Transporter ◽

Abc Transporters ◽

Cholesterol Metabolism ◽

Current Knowledge ◽

Large Family ◽

Cholesterol Homeostasis

AbstractThe ATP-binding cassette (ABC) transporter superfamily is a large family of proteins that transport specific molecules across membranes. These proteins are associated with both cholesterol metabolism and Alzheimer’s disease (AD). Cholesterol homeostasis has a key role in AD, and ABC transporters are important mediators of lipid transportation. Emerging evidence suggests that decreased expression and hypofunction of ABC transporters are crucial to the occurrence and development of AD. In the present article, we review the current knowledge regarding ABC transporters and speculate on their role in the pathogenesis of AD.

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Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice

eLife ◽

10.7554/elife.22409 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 9

Author(s):

Claudia Villani ◽

Giuseppina Sacchetti ◽

Renzo Bagnati ◽

Alice Passoni ◽

Federica Fusco ◽

...

Keyword(s):

Rett Syndrome ◽

Potential Role ◽

Cholesterol Metabolism ◽

Cholesterol Homeostasis ◽

Motor Deficits ◽

Brain Cholesterol ◽

Background Strain ◽

Cholesterol Levels ◽

The Brain

Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.

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Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative

Journal of Alzheimer s Disease ◽

10.3233/jad-215091 ◽

2021 ◽

pp. 1-10

Author(s):

Michelle M. Dunk ◽

Ira Driscoll ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Total Cholesterol ◽

Cholesterol Metabolism ◽

Apoe Genotype ◽

Control Group ◽

Cholesterol Levels ◽

Related Risk ◽

E4 Allele

Background: APOE ɛ4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (ps < 0.05, F-statistics>10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

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Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C

Journal of Neurodegenerative Diseases ◽

10.1155/2013/407903 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Yoon Sun Chun ◽

Hyun Geun Oh ◽

Myoung Kyu Park ◽

Tae-Wan Kim ◽

Sungkwon Chung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phospholipase C ◽

Cholesterol Level ◽

Cholesterol Metabolism ◽

Membrane Cholesterol ◽

Neuronal Dysfunction ◽

Carrier System ◽

Cholesterol Levels

Cerebral elevation of 42-residue amyloid β-peptide (Aβ42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect Aβ generation, the role of cholesterol in the pathogenesis of AD is not clear yet. Recently, we have shown that increased membrane cholesterol levels downregulates phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of phospholipase C (PLC). In this study, we tested whether membrane cholesterol levels may affect the Aβ42 production via changing PIP2 levels. Increasing membrane cholesterol levels decreased PIP2 and increased secreted Aβ42. Supplying PIP2, by using a PIP2-carrier system, blocked the effect of cholesterol on Aβ42. We also found that cholesterol increased the expressions of β1 and β3 PLC isoforms (PLCβ1, PLCβ3). Silencing the expression of PLCβ1 prevented the effects of cholesterol on PIP2 levels as well as on Aβ42 production, suggesting that increased membrane cholesterol levels increased secreted Aβ42 by downregulating PIP2 via enhancing the expression of PLCβ1. Thus, cholesterol metabolism may be linked to Aβ42 levels via PLCβ1 expression and subsequent changes in PIP2 metabolism.

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