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Scholarly Works (2 results)

Thesis
Peer Reviewed

Rhythmic Regulation of DNA Methylation by BMAL1 is Altered in Alzheimer's Disease

Alexeeva, Arina
Advisor(s): Desplats, Paula

UC San Diego Electronic Theses and Dissertations (2018)

Alzheimer’s disease (AD) is on the rise in the U.S. and has no current cure or effective, lasting therapy. AD is associated with circadian and epigenetic disruptions, both of which may contribute to the neurodegeneration, cognitive impairment and dementia characteristic of AD. Epigenetic machinery is known to regulate the circadian clock, however preliminary studies in our lab have suggested that circadian regulators may also regulate epigenetic machinery. We explored the relationship between DNA methylation and circadian molecular mechanisms in the context of AD. Specifically, we investigated the action of circadian regulator Bmal1 in mediating the expression of DNA methyltransferase 1 (Dnmt1) in rat neurons. We hypothesized that a) Dnmt1 is expressed rhythmically in neurons, that b) Bmal1 acts as a transcription factor to regulate oscillation of Dnmt1, and that c) AD pathology alters this rhythmicity and regulation of Dnmt1. To generate an in vitro model of AD, amyloid precursor protein (APP) was overexpressed in adult rat hippocampal neurons. Dnmt1 transcription in the rat neurons was indeed found to be rhythmic and appeared to be altered in APP-overexpressing neurons. Additionally, we showed that Bmal1 does rhythmically bind to canonical E-boxes present at the Dnmt1 gene and that this binding is largely reduced with APP-overexpression. Our results not only provide an example of direct circadian control of DNA methylation in neurons, but also support our hypothesis that AD pathology disrupts this regulation. Defining the mechanism behind this relationship may further elucidate the molecular effects of AD pathology, as well as reveal possible circadian targets as future AD therapeutics.

Cover page: Rhythmic Regulation of DNA Methylation by BMAL1 is Altered in Alzheimer's Disease

Article
Peer Reviewed

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

UC San Diego Previously Published Works (2018)

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-β, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aβ protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aβ levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aβ in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aβ and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Cover page: Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy