Remembering your A, B, C's: Alzheimer's disease and ABCA1

Lewandowski, Cutler T.; Laham, Megan S; Thatcher, Gregory R. J.

doi:10.1016/j.apsb.2022.01.011

Cited by 25 publications

(22 citation statements)

References 391 publications

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“…Despite being present in both neurons and astrocytes, LDLR is most highly expressed in glia, whereas LRP1 is more highly expressed in neurons [ 61 , 62 , 63 , 64 , 65 ]. Specifically, LRP1 is a critical source of cholesterol for neurite outgrowth, synaptogenesis, and remodeling; however, it may also exert negative feedback to limit the intracellular cholesterol concentration [ 66 , 67 ]. Regarding VLDLR and ApoER2, they are structurally very similar to the LDLR; however, they mainly bind other ligands involved in neurodevelopment and synaptic functions, such as reelin [ 68 ].…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

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Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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“…On the other hand, lipid abnormalities and hypertriglyceridemia are one of the common side-effects in patients treated with bexarotene. Bexarotene can elicit lipogenic side effects [67]. Other RXR agonists could elevate the "good" high-density lipoprotein and the "bad" triglycerides [68].…”

Section: Discussionmentioning

confidence: 99%

RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect

Wang

Zhang

et al. 2023

Cells

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Retinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide’s anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.

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“…Reduced ABCA1 expression or activity is implicated in AD and other disorders. Therefore, therapeutic approaches to boost ABCA1 activity are promising [ 73 ]. It has been reported that RSV effects on cholesterol efflux via the overexpression of ABCA1 protein are mediated through the adenosine A 2A receptor in THP-1 macrophages and HAEC cells [ 74 , 75 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice

Sánchez-Melgar

Izquierdo-Ramírez

Griñán-Ferré

et al. 2022

IJMS

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Cholesterol metabolism seems dysregulated and linked to amyloid-β (Aβ) formation in neurodegeneration, but the underlying mechanisms are poorly known. Resveratrol (RSV) is a polyphenol with antioxidant activity and neuroprotective properties. Here, we analyzed the effect of age and RSV supplementation on cholesterol metabolism in the brain and blood serum, and its potential link to Aβ processing, in SAMP8 mice—an animal model of aging and Alzheimer’s disease. In the brain, our results revealed an age-related increase in ApoE and unesterified cholesterol in the plasma membrane whereas LDL receptor, HMG-CoA reductase, HMG-CoA-C1 synthase, and ABCA1 transporter remained unaltered. Furthermore, BACE-1 and APP gene expression was decreased. This dysregulation could be involved in the amyloidogenic processing pathway of APP towards Aβ formation. In turn, RSV exhibited an age-dependent effect. While levels of unesterified cholesterol in the plasma membrane were not affected by RSV, several participants in cholesterol uptake, release, and de novo synthesis differed, depending on age. Thus, RSV supplementation exhibited a different neuroprotective effect acting on Aβ processing or cholesterol metabolism in the brain at earlier or later ages, respectively. In blood serum, HDL lipoprotein and free cholesterol were increased by age, whereas VLDL and LDL lipoproteins remained unaltered. Again, the protective effect of RSV by decreasing the LDL or increasing the HDL levels also seems to depend on the intervention’s moment. In conclusion, age is a prominent factor for cholesterol metabolism dysregulation in the brain of SAMP8 mice and influences the protective effects of RSV through cholesterol metabolism and Aβ processing.

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Remembering your A, B, C's: Alzheimer's disease and ABCA1

Cited by 25 publications

References 391 publications

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect

Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice

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