ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease

Li, Yonghe; Macyczko, Jesse R.; Liu, Chia-Chen; Bu, Guojun

doi:10.1016/j.neurobiolaging.2022.03.011

Cited by 28 publications

(11 citation statements)

References 140 publications

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“…Figure 2F presents another instance of cell-type specificity as APOE is expressed in 6 different cell types but only shows a novel cis -eQTL effect in microglia, where eQTL detection is relatively underpowered compared to other cell types. This is interesting as APOE is one of the key genes upregulated in Disease Associated Microglia (DAM) that have been described in amyloid proteinopathy models ( 19 ). This APOE locus variant, rs2288911, is associated with AD according to summary statistics of previous GWAS ( p = 1.0 × 10 -12 and p = 6.0 × 10 -10 ) ( 20 , 21 ).…”

Section: Resultsmentioning

confidence: 99%

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

Fujita

Gao

Zeng

et al. 2022

Preprint

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The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression incis(cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influencesAPOEexpression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect ofAPOEε4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only aTMEM106Bvariant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimer's, Parkinson's, schizophrenia, and educational attainment.

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Section: Resultsmentioning

confidence: 99%

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

Fujita

Gao

Zeng

et al. 2022

Preprint

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“…For instance, the uptake and degradation of Aβ by astrocytes were altered by modulating levels of LDL-R in the brain [ 70 ] and a higher expression of LDL-R is convenient for the clearance of toxic substances such as Aβ proteins. The links between lipids metabolism and Alzheimer’s disease reveals apolipoprotein E as a key factor [ 39 , 40 , 71 ], and these studies demonstrate that upregulation of LDL-R can lead to a reduction in ApoE and alleviation of AD pathologies (reviewed in [ 72 ]). The high level of LDL-R might likely elevate the clearance rate of Aβ and decrease the Aβ level in the SAMP8 brain.…”

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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“…Genetically modified mouse models revealed that a number of these properties can be ameliorated by ApoE gene inactivation. These observations led to the suggestion that apoE4 reduction may be a promising therapeutic strategy for Alzheimer’s disease management [ 178 ]. However, specific apoE reduction in the brain without affecting apoE level and its beneficial properties peripherally would be an enormous challenge.…”

Section: Role Of Apoe In Neurological Health and Diseasementioning

confidence: 99%

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

Alagarsamy

Jaeschke

Hui

2022

IJMS

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A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.

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ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease

Cited by 28 publications

References 140 publications

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

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

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

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