INTRODUCTION Circadian alterations are prevalent in Alzheimer’s disease (AD) and may contribute to cognitive impairment, behavioral symptoms and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD. METHODS We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD. RESULTS DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles. DISCUSSION Our results indicate that cycles of DNA methylation contribute to the regulation BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.
HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.
CHI3L1) and pre-(synaptophysin) and post-synaptic (PSD95) markers were measured by RT-PCR and ELISA, respectively. Results: In AD, relative to controls, there was a significant increase in levels of Ab (p<0.001), pTau (p<0.001), CHI3L1 (p¼0.015) and microglial markers related to phagocytosis (CD68, p¼0.037), antigen presentation (HLA-DR, p¼0.044) and immune response (FcgRI, p¼0.002). We also observed a significant association between FcgRIIa and FcgRIII and CHI3L1 and FcgRIII in AD (AD-and AD+); and between FcgRI and FcgRIII in ASI cohorts (Ctrl+ and AD+). We showed that ASI significantly decreases the expression of FcgRIII (p¼0.03) and elevates the expression of anti-inflammatory genes IL4R (p¼0.04) and CHI3L1 (p¼0.012) in AD cases (AD+ vs. AD-). ASI did not affect Ab, pTau or synaptic proteins. Conclusions: Our findings confirm our previous observations as well as genetic studies that indicate a role for microglia in AD. Interestingly, ASI appears to promote immunosuppression without affecting AD pathology or synaptic proteins. This may be driven at least in part through communication between microglial cells via the FcgR, key receptors involved in the peripheral immune response.Background: Inflammation is a major component of Alzheimer's disease (AD) pathology, implicated in amyloid deposition and associated with dementia and cognitive impairment. Emerging data show that altered epigenetic mechanisms also contribute to neurodegeneration. AD postmortem brains have acceleration of agerelated methylation changes and genes associated with increased disease susceptibility are differentially methylated in AD, even at early stages. Although epigenetic factors have been implicated in the production of pro-inflammatory cytokines, the role of DNA methylation on neuroinflammation is yet poorly understood. The goal of this study was to investigate the methylation status of inflammation-related genes in AD brains, progressing from mild cognitive impairment (MCI) to dementia. Methods: Genome-wide DNA methylation was profiled on postmortem frontal-cortex samples from MCI and AD cases and age and sex-matched control subjects (n¼24 cases /group) using Human Methylation450k microarray. Analysis of differential methylation in MCI and AD brains was performed in minfi using bump-humpting and block finder functions. Changes in methylation at individual CpGs were determined with Partek Genomics Suite computing for clinical diagnosis, gender and age in multivariate ANOVA analysis. Direct effects of DNA methylation changes on transcription of inflammatory genes were tested on human primary microglial cultures. Results: DNA methylation alterations were more prominent in MCI, with 35 differentially methylated blocks (DMBs) identified at q<0.05, in contrast to 15 DMBs in AD brains. GSEA analysis of DMBs showed significant enrichment for the common regulatory factors TCF3/LEF1, which mediates signals from TNFa; NRF1, implicated in insulin resistance, diabetes and inflammatory pathways; and NFAT, that mediates inflammation and calcium imb...
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