A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

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

Antioxidants ◽

10.3390/antiox10121890 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1890

Author(s):

Erica Staurenghi ◽

Serena Giannelli ◽

Gabriella Testa ◽

Barbara Sottero ◽

Gabriella Leonarduzzi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholesterol Metabolism ◽

Amyloid Β ◽

Physiological Role ◽

Cholesterol Oxidation ◽

Peripheral Tissues ◽

Functional Changes ◽

Brain Cholesterol ◽

The Impact

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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Faculty Opinions recommendation of Relationships between tau and glucose metabolism reflect alzheimer's disease pathology in cognitively normal older adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733457144.793547250 ◽

2018 ◽

Author(s):

Daniela Perani

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Cognitively Normal

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Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00759-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Malo Gaubert ◽

Catharina Lange ◽

Antoine Garnier-Crussard ◽

Theresa Köbe ◽

Salma Bougacha ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Glucose Metabolism ◽

Corpus Callosum ◽

Gray Matter ◽

Fdg Pet ◽

White Matter Hyperintensities ◽

Gray Matter Volume ◽

Matter Volume

Abstract Background White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

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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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