Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development.

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

Biochemical Society Transactions ◽

10.1042/bst0381021 ◽

2010 ◽

Vol 38 (4) ◽

pp. 1021-1025 ◽

Cited By ~ 35

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

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

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.

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Liver Bile Acid Changes in Mouse Models of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22147451 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7451

Author(s):

Harpreet Kaur ◽

Drew Seeger ◽

Svetlana Golovko ◽

Mikhail Golovko ◽

Colin Kelly Combs

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Bile Acid ◽

Bile Acids ◽

Cholesterol Metabolism ◽

Amyloid Β ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Liver Cholesterol ◽

Bile Acid Metabolism

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

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Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

Scientific Reports ◽

10.1038/s41598-021-94706-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna A. Lauer ◽

Daniel Janitschke ◽

Malena dos Santos Guilherme ◽

Vu Thu Thuy Nguyen ◽

Cornel M. Bachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Lipid Homeostasis ◽

Medical Surveillance ◽

Shotgun Lipidomics ◽

App Processing ◽

Cognitive Improvement ◽

The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models

10.26686/wgtn.17148107 ◽

2021 ◽

Author(s):

◽

Rosemary Heathcott

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disease ◽

Cell Line ◽

Cholesterol Metabolism ◽

Neurodegenerative Disorder ◽

Heparan Sulphate ◽

Amyloid Β ◽

Neuronal Cell ◽

Lysosomal Storage

<p>Heparan sulphate proteoglycans (HSPG) are central to numerous processes of the mammalian cell. The highly charged negative side chains of the heparan sulphate (HS) oligosaccharides are essential for the regulatory and structural functions of the proteoglycan. Synthetic HS compounds have potential therapeutic value due to their ability to mimic naturally occurring HS. Niemann-Pick disease type C (NPC) is a fatal childhood neurodegenerative disease with characteristic cholesterol and sphingolipid accumulation in the late endosome or lysosome. Alzheimer’s disease, another neurodegenerative disorder, shares alterations of cholesterol and amyloid β metabolism with NPC. In this study,a set of novel heparan sulphate compounds with a range of structures and oligosaccharide side groups with a variety of degrees of sulphation was investigated with regards to their effects on cholesterol and amyloid β metabolism in cell line models of these two diseases. Fluorescent staining of cholesterol and confocal microscopy showed highly sulphated compounds reduce the accumulation of cholesterol in the perinuclear lysosomal storage organelles in patient fibroblast cell lines. The compounds had no effect on secreted amyloid β levels or amyloid precursor protein levels in a neuronal cell line model of early onset Alzheimer’s disease. The mechanism of cholesterol reduction is unclear but may be related to a reduction in HSPG-associated endocytosis of LDL/cholesterol.</p>

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Perphenazine-macrocycle conjugates divert Aβ42 towards non-toxic aggregates by monomer sequestration

10.1101/2020.11.16.384248 ◽

2020 ◽

Author(s):

Sarah R Ball ◽

Julius S P Adamson ◽

Michael A Sullivan ◽

Manuela R Zimmermann ◽

Victor Lo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nmr Spectroscopy ◽

Kinetic Analysis ◽

Amyloid Β ◽

Dimensional Structure ◽

Amyloid Β Peptide ◽

Monomeric Form ◽

Starting Point ◽

The Impact

AbstractThe amyloid-β peptide, the main protein component of amyloid plaques in Alzheimer’s disease, plays a key role in the neurotoxicity associated with the condition through the formation of small toxic oligomer species which mediate the disruption of calcium and glutamate homeostasis. The lack of therapeutic benefit associated with removal of mature amyloid-β fibrils has focused attention on the toxic oligomeric species formed during the process of fibril assembly. Here, we present the design and synthesis of a family of perphenazine-macrocyle conjugates. We find that two-armed perphenazine-cyclam conjugates divert the monomeric form of the amyloid-β peptide away from the amyloidogenic pathway into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. This strategy prevents the formation of damaging amyloid oligomers. Kinetic analysis of the effects of these compounds on the assembly pathway, together with NMR spectroscopy, identifies rapid monomer sequestration as the underlying neuroprotective mechanism. The ability to specifically target the monomeric form of amyloid-β allows for further understanding of the impact of the multiple species formed between peptide biogenesis and plaque deposition. The modular, three-dimensional structure of these compounds provides a starting point for the design of more potent modulators of this amyloid-forming peptide, and can be adapted to probe the protein self-assembly pathways associated with other proteinopathies.Significance statementThe aggregation pathway of the amyloid-β (Aβ) peptide in Alzheimer’s disease is complex and involves multiple different species. An inability to isolate and study the impact of distinct Aβ species has undermined efforts to develop effective therapies. To address this issue, we have developed a series of molecules that specifically sequester the monomeric form of the highly aggregation-prone Aβ42 peptide. Interaction with these molecules diverts Aβ42 from the amyloidogenic pathway and prevents formation of toxic oligomeric species. We use kinetic analysis and NMR spectroscopy to identify rapid monomer sequestration as the underlying neuroprotective mechanism. Future rational development of these molecules and characterisation of their interactions with Aβ will delineate the impact of different Aβ oligomers on neurobiology and pathology.

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Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.666710 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cátia R. Lopes ◽

Rodrigo A. Cunha ◽

Paula Agostinho

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

The Elderly ◽

Synaptic Function ◽

Morphological Alterations ◽

Functional Changes ◽

A2a Receptors ◽

Novel Therapeutic Strategies

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

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