DNA Methylation in the Apolipoprotein-A1 Gene is Associated with Episodic Memory Performance in Healthy Older Individuals

Lazarus, Jessica; Mather, Karen A.; Armstrong, Nicola J.; Song, Fei; Poljak, Anne; Thalamuthu, Anbupalam; Lee, Teresa; Kochan, Nicole A.; Brodaty, Henry; Wright, Margaret J.; Ames, David; Sachdev, Perminder S.; Kwok, John B.

doi:10.3233/jad-141314

Cited by 24 publications

(20 citation statements)

References 27 publications

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“…The Apo A-1 proteoforms b and d were increased in serum and decreased in CSF, whereas Apo A-1 proteoform c increased both in CSF and serum. Our results can be related to a recent study on the methylation of the promoter region of the APOA1 gene [19]. This epigenetic modification promotes the switch-off of the gene even though not associated with a protein decrement in serum.…”

Section: Discussionsupporting

confidence: 85%

“…Recently, a negative association with memory performance has been related to increased DNA methylation and higher serum levels of Apo A-1 [19]. …”

Section: Discussionmentioning

confidence: 99%

“…However, recent results on Apo A-1 levels and their correlation with dementia appear contradictory. In AD, Apo A-1 levels were described as decreased or unchanged [7, 19], whereas hyper-methylation of the promoter region and the concurrent switch-off of the APOA1 gene, recently documented [19], would suggest a decrease of this protein in AD. However hyper-methylation was not supported by ELISA results, leaving the question of Apo A-1 abundance still open.…”

Section: Introductionmentioning

confidence: 99%

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Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms

et al. 2017

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In the diagnosis of Alzheimer’s disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha β-amyloid (Aβ) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several “confounding” factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient’s variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV<20%, AUC>0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A-1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression.

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Section: Discussionsupporting

confidence: 85%

“…Recently, a negative association with memory performance has been related to increased DNA methylation and higher serum levels of Apo A-1 [19]. …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms

et al. 2017

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“…In both cohorts, the platform was the same, methylation was measured in cord blood, exposure was categorized in a similar way (any smoking by the mother during pregnancy), Caucasian/European ancestry participants were included in the analyses (subset of NEST), and the statistical model and covariates were aligned. This approach also has been used in several studies that first identified CpG sites using arrays, and then validated the loci using PSQ (Breton et al 2009; Devaney et al 2015; Lazarus et al 2015). …”

Section: Approaches For Validating/replicating Loci That Emerge As Tomentioning

confidence: 99%

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Breton

Marsit

Faustman

et al. 2017

Environ Health Perspect

237

159

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Background:Characterization of the epigenome is a primary interest for children’s environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Objectives:Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children’s Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.Methods:We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.Discussion:A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children’s health.Conclusion:The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.Citation:Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. 2017. Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies: the Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group. Environ Health Perspect 125:–526; http://dx.doi.org/10.1289/EHP595

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“…Since SR-BI has already been identified as a major receptor for HDL (with their major apolipoprotein [apo] A-I ) as well as for the earlier-described LCM/ND nanoemulsion, this multitasking lipid nanoemulsion can arguably serve as a targeted, apo A-I-based, (SR-BI mediated) therapeutic agent for Alzheimer's disease Hottman et al 2014;Robert et al 2016Robert et al , 2017cf. Choi et al 2016;Kitamura et al 2017;Lazarus et al 2015;Ma et al 2015;Slot et al 2017;Velagapudi et al 2017;Yin et al 2014).…”

Section: Targeting Senile Endothelium Brain Biometal (Fe Ca) Dyshommentioning

confidence: 99%

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

D'Arrigo

2018

Advances in Colloid and Interface Science

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Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such filmstabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

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DNA Methylation in the Apolipoprotein-A1 Gene is Associated with Episodic Memory Performance in Healthy Older Individuals

Abstract: Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults.

Cited by 24 publications

References 27 publications

Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms

Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

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