Alzheimer’s Disease Risk Genes and Lipid Regulators

Gaamouch, Farida El; Jing, Ping; Xia, Jiahong; Cai, Dongming

doi:10.3233/jad-160169

Cited by 53 publications

(39 citation statements)

References 194 publications

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“…Comparable changes have been previously reported, in a study of aging cervical spinal cord, that were associated with perturbation of cholesterol homeostasis (increased white matter cholesterol ester concentrations) and inflammatory activation in the cervical spinal cord [47]. Age-related changes in CNS cholesterol metabolism are believed to play a key role in the development of some forms of Alzheimer’s disease and other degenerative disorders [48]. …”

Section: Discussionmentioning

confidence: 75%

Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Galbavy

Kaczocha

et al. 2017

Immun Ageing

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BackgroundWe have previously reported elevated expression of multiple pro-inflammatory markers in the lumbar spinal cord (LSC) of middle-aged male rats compared to young adults suggesting a para-inflammatory state develops in the LSC by middle age, a time that in humans is associated with the greatest pain prevalence and persistence. The goal of the current study was to examine the transcriptome-wide gene expression differences between young and middle aged LSC.MethodsYoung (3 month) and middle-aged (17 month) naïve Fisher 344 rats (n = 5 per group) were euthanized, perfused with heparinized saline, and the LSC were removed.Results~70% of 31,000 coding sequences were detected. After normalization, ~ 1100 showed statistically significant differential expression. Of these genes, 353 middle-aged annotated genes differed by > 1.5 fold compared to the young group. Nearly 10% of these genes belonged to the microglial sensome. Analysis of this subset revealed that the principal age-related differential pathways populated are complement, pattern recognition receptors, OX40, and various T cell regulatory pathways consistent with microglial priming and T cell invasion and modulation. Many of these pathways substantially overlap those previously identified in studies of LSC of young animals with chronic inflammatory or neuropathic pain.ConclusionsUp-modulation of complement pathway, microglial priming and activation, and T cell/antigen-presenting cell communication in healthy middle-aged LSC was found. Taken together with our previous work, the results support our conclusion that an incipient or para-inflammatory state develops in the LSC in healthy middle-aged adults.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-017-0091-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 75%

Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Galbavy

Kaczocha

et al. 2017

Immun Ageing

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“…It is mainly idiopathic, with late-onset affecting more than 90% of cases [1]. It is classified, across its pathological hallmarks, as a tauopathy-characterized by hyperphosphorylated, filamentous tau aggregates prior to microtubule collapse—a major requisite for the formation of neurofibrillary tangles [2,3].…”

Section: Introductionmentioning

confidence: 99%

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

Manalo

Silvestre²,

Barbosa³

et al. 2017

Biomedicines

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Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer’s disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically the leaves, using in vitro and in vivo approaches. Coconut leaf extract (CLE) was screened for antioxidant and AChE inhibitory properties in vitro and therapeutic effects in two strains of transgenic Caenorhabditis elegans expressing amyloid-β1–42 (Aβ1-42) in muscle cells. CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid, and an AChE inhibitory activity that is 131-fold less compared to Rivastigmine. Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31% in CL2006 in a dose-independent manner, and reduced the percentage of paralyzed nematodes at the lowest concentration of CLE (159.38 μg/mL), compared to dH2O/vehicle (control). Phytochemical analysis detected glycosides, anthocyanins, and hydrolyzable tannins in CLE, some of which are known to be anti-amyloidogenic. Taken together, these findings suggest that CLE metabolites alternatively decrease AB1–42 aggregation and paralysis prevalence independently of free radical scavenging and AChE inhibition, and this warrants further investigation on the bioactive compounds of CLE.

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“…Due to the SNPs rs429358 and rs7412 in the APOE gene, three haplotypes are formed: e2 (T allele rs7412 and T allele rs429358), e3 (C allele rs7412 and T allele rs429358), and the e4 allele (C allele rs7412 and C allele rs429358) (Morgan and Carrasquillo, 2013). The APOE protein and Clusterin (CLU) protein, another apolipoprotein, carries cholesterol among brain cells (El Gaamouch et al, 2016) and acts on the clearance of Ab peptides (Rizzi et al, 2009). The CLU or Apolipoprotein J (APOJ) protein (Rizzi et al, 2009) is associated with a neuroprotective effect in AD (Schrijvers et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The combined risk effect among BIN1, CLU, and APOE genes in Alzheimer’s disease

et al. 2020

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Genome-wide associations studies (GWAS) are detecting new variants associated with late-onset of Alzheimer's disease (LOAD), a multifactorial neurodegenerative disorder. The variants rs744373 BIN1, rs11136000 CLU and rs3764650 ABCA7 uncovered by GWAS led to different AD pathways, such as metabolism, trafficking and endocytosis of lipids and inflammation. However, most of the association studies did not replicate these variants with significance. This could be due to a small power effect evident when these variants are tested independently with LOAD. Therefore, we aimed to investigate whether the combination of different variants would additively modify the risk of association with LOAD that is observed in GWAS. We performed an association study testing pairwise variants in metabolism, trafficking and endocytosis of lipid (rs429358 and rs7412 APOE, rs744373 BIN1, rs3764650 ABCA7 and rs11136000 CLU) pathways with LOAD in samples from southeastern Brazil. Our data suggest a risk effect for LOAD between APOE with CLU and APOE with BIN1 genes.

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Alzheimer’s Disease Risk Genes and Lipid Regulators

Cited by 53 publications

References 194 publications

Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

The combined risk effect among BIN1, CLU, and APOE genes in Alzheimer’s disease

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