PLD3 epigenetic changes in the hippocampus of Alzheimer’s disease

Abstract

BackgroundWhole-exome sequencing has revealed a rare missense variant in PLD3 gene (rs145999145) to be associated with late onset Alzheimer’s disease (AD). Nevertheless, the association remains controversial and little is known about the role of PLD3 in AD. Interestingly, PLD3 encodes a phospholipase that may be involved in amyloid precursor protein (APP) processing. Our aim was to gain insight into the epigenetic mechanisms regulating PLD3 gene expression in the human hippocampus affected by AD.ResultsWe assessed PLD3 mRNA expression by qPCR and protein levels by Western blot in frozen hippocampal samples from a cohort of neuropathologically confirmed pure AD cases and controls. Next, we profiled DNA methylation at cytosine-phosphate-guanine dinucleotide (CpG) site resolution by pyrosequencing and further validated results by bisulfite cloning sequencing in two promoter regions of the PLD3 gene. A 1.67-fold decrease in PLD3 mRNA levels (p value < 0.001) was observed in the hippocampus of AD cases compared to controls, and a slight decrease was also found by Western blot at protein level. Moreover, PLD3 mRNA levels inversely correlated with the average area of β-amyloid burden (tau-b = − 0,331; p value < 0.01) in the hippocampus. A differentially methylated region was identified within the alternative promoter of PLD3 gene showing higher DNA methylation levels in the AD hippocampus compared to controls (21.7 ± 4.7% vs. 18.3 ± 4.8%; p value < 0.05).ConclusionsPLD3 gene is downregulated in the human hippocampus in AD cases compared to controls. Altered epigenetic mechanisms, such as differential DNA methylation within an alternative promoter of PLD3 gene, may be involved in the pathological processes of AD. Moreover, PLD3 mRNA expression inversely correlates with hippocampal β-amyloid burden, which adds evidence to the hypothesis that PLD3 protein may contribute to AD development by modifying APP processing.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0547-3) contains supplementary material, which is available to authorized users.

Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

“…Aside from SNPs inducing non-sense mutations or splice variations, LOAD risk factor protein expression can be affected by the (LO) AD pathology itself. As an example, PLD3 transcription is altered through AD-linked epigenetic disturbances, highlighting the potential implication of such regulations in the control of LOAD risk factor expression [32]. Hence, even patients without a LOAD risk SNP could be affected by the associated neuronal endolysosomal stress.…”

Epigenetic modulation during hippocampal development (Review)

“…This may be a mechanism for persistent hyperexcitability in chronic epilepsy. Similarly, Blanco-Luquin et al showed that the downregulation of expression caused by hypermethylation of the phospholipase D family, member 3 gene is closely associated with late-onset AD (58). Studies have suggested that childhood neglect or abuse can cause methylation and histone modifications in the child's hippocampal glucocorticoid receptor promoter region, which reduces the child's hippocampal glucocorticoid receptor expression and increases the adulthood stress response leading to depression and anxiety (59,60).…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…Ma et al find that UQCRC1 is highly methylated in patients with AD by studying peripheral blood samples of AD, suggesting that inflammation and oxidative stress may contribute to AD ( 50 ). The DNA methylation level of PLD3 is increased and correlated with hippocampal Aβ in AD hippocampus compared to controls ( 51 ). A lower DNA methylation level at TREM2 is observed in AD patients and associated with TREM2 mRNA expression, which may be a biomarker for AD ( 52 ).…”