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Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer’s disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.

Considerable evidence indicates that cholesterol oxidation products, named oxysterols, play a key role in several events involved in Alzheimer’s disease (AD) pathogenesis. Although the majority of oxysterols causes neuron dysfunction and degeneration, 24-hydroxycholesterol (24-OHC) has recently been thought to be neuroprotective also. The present study aimed at supporting this concept by exploring, in SK-N-BE neuroblastoma cells, whether 24-OHC affected the neuroprotective SIRT1/PGC1α/Nrf2 axis. We demonstrated that 24-OHC, through the up-regulation of the deacetylase SIRT1, was able to increase both PGC1α and Nrf2 expression and protein levels, as well as Nrf2 nuclear translocation. By acting on this neuroprotective pathway, 24-OHC favors tau protein clearance by triggering tau ubiquitination and subsequently its degradation through the ubiquitin–proteasome system. We also observed a modulation of SIRT1, PGC1α, and Nrf2 expression and synthesis in the brain of AD patients with the progression of the disease, suggesting their potential role in neuroprotection. These findings suggest that 24-OHC contributes to tau degradation through the up-regulation of the SIRT1/PGC1α/Nrf2 axis. Overall, the evidence points out the importance of avoiding 24-OHC loss, which can occur in the AD brain, and of limiting SIRT1, PGC1α, and Nrf2 deregulation in order to prevent the neurotoxic accumulation of hyperphosphorylated tau and counteract neurodegeneration.

The strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography–mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.

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.

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.

Background: Exaggerated Toll-like receptor (TLR)-mediated immune and inflammatory responses play a role in inflammatory bowel diseases. This report deals with the ability of a mixture of oxysterols widely present in cholesterol-rich foods to induce in vitro intestinal inflammation through TLR up-regulation. The anti-inflammatory action of four cocoa bean shell (CBS) extracts with different polyphenol content, was tested. Methods: Differentiated intestinal CaCo-2 cells were treated with a dietary oxysterol mixture (Oxy-mix) (60 µM). The expression and activation of TLR2 and TLR4, as well as the production of their downstream signaling effectors IL-8, IFNβ and TNFα were analyzed in the presence or absence of TLR antibodies. Honduras CBS extracts were characterized for their polyphenol contents; their anti-inflammatory action was analyzed in CaCo-2 cells treated with Oxy-mix. Results: Oxysterol-dependent TLR-2 and TLR4 over-expression and activation together with cytokine induction were abolished by blocking TLRs with specific antibodies. Polyphenol-rich CBS extracts consisting of high quantities of (−)-epicatechin and tannins also prevented TLR induction. Conclusions: TLR2 and TLR4 mainly contribute to inducing oxysterol-dependent intestinal inflammation. The fractionation method of CBS allowed the recovery of fractions rich in (−)-epicatechin and tannins able to counteract oxysterol-induced inflammation, thus highlighting the beneficial biological potential of specific CBS extracts.