The APOE Gene is Differentially Methylated in Alzheimer’s Disease

Foraker, Jessica; Millard, Steven P.; Leong, Lesley; Thomson, Zachary; Chen, Sunny; Keene, C. Dirk; Bekris, Lynn M.; Yu, Chang‐En

doi:10.3233/jad-143060

Cited by 113 publications

(129 citation statements)

References 33 publications

(35 reference statements)

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“…Multiple control and enhancer elements embedded within this genomic region regulate tissue- and cell-specific and hormonal- and metabolite-mediated regulation [43–52]. DNA methylations within two such elements of the APOE gene control tissue-, cell- and genotype-specific APOE and TOMM40 expression [53, 54]. Cholesterol stimulates APOE expression, and this is mediated by LXR response elements within APOE enhancer elements [39, 55, 56].…”

Section: Discussionmentioning

confidence: 99%

The effects of PPARγ on the regulation of the TOMM40 - APOE - C1 genes cluster

Subramanian¹,

Gottschalk²,

Kim³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer’s disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear transcription factor that plays a role in human complex traits that are also genetically associated with the chromosome 19q13.32 region. Here, we study the effects of PPARγ on the regional expression regulation of the genes clustered within chromosome 19q13.32, specifically TOMM40, APOE, and APOC1, applying two complementary approaches. Using the short hairpin RNA (shRNA) method in the HepG2 cell-line we knocked down PPARγ expression and measured the effect on mRNA expression. We discovered PPARγ knock down increased the levels of TOMM40-, APOE-, and APOC1-mRNAs, with the highest increase in expression observed for APOE-mRNA. To complement the PPARγ knockdown findings we also examined the effects of low doses of PPARγ agonists (nM range) on mRNA expression of these genes. Low (nM) concentrations of Pioglitazone (Pio) decreased transcription of TOMM40, APOE and APOC1 genes, with the lowest mRNA levels for each gene observed at 1.5 nM. Similar to the effect of PPARγ knockdown, the strongest response to Pioglitazone was also observed for APOE-mRNA, and Rosiglitazone (Rosi), another PPARγ agonist, produced results that were consistent with these. In conclusion, our results further established a role for PPARγ in regional transcriptional regulation of chr19q13.32, underpinning the association between PPARγ, the chr19q13.32 genes cluster, and human complex traits and disease.

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Section: Discussionmentioning

confidence: 99%

The effects of PPARγ on the regulation of the TOMM40 - APOE - C1 genes cluster

Subramanian¹,

Gottschalk²,

Kim³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…It is believed that Alzheimer's is a complex disease where several factors contribute to its development. The uttermost risk factors and causes for AD include age, lifestyle, environmental factors, family history, and bearing the Apolipoprotein E ( APOE )‐ε4 gene . Moreover, genetic mutations are one of the causative factors of AD, as AD genes were reported to be expressed on different chromosomes causing subsequent mutation in the expressed gene product .…”

Section: Introductionmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

226

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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“…The ApoE-ε4-mediated AD progression is not well understood but it is being postulated that ApoE-ε4 results in increased Aβ deposition and its faulty clearance [31]. Differentially ApoE-ε4 DNA methylation is reported in AD so that epigenetic alteration results in AD onset/progression [32]. Aβ accumulation/production increases due to the elevated levels of β-secretase enzyme, β-APP cleaving enzyme and its substrate APP following glucocorticoid administration [29].…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Ahmad

Fatima

Mondal³

2019

Neuropsychobiology

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Alzheimer’s disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.

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The APOE Gene is Differentially Methylated in Alzheimer’s Disease

Cited by 113 publications

References 33 publications

The effects of PPARγ on the regulation of the TOMM40 - APOE - C1 genes cluster

The effects of PPARγ on the regulation of the TOMM40 - APOE - C1 genes cluster

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

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