Browsing by Subject "Apolipoprotein E"

Now showing 1 - 3 of 3
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    AB affects apoE transcriptionally through the activation of B-AR, cAMP and AP-2
    (2009-09) Rossello, Ximena Serenella
    Two key players in the development of Alzheimer’s disease (AD) are amyloid beta protein (Aβ) and apolipoprotein E (apoE). We and others have reported that Aβ elevates apoE protein levels in astrocytes, which in turn could alter lipid trafficking and cell function. The mechanism for the Aβ-induced increase in apoE levels is not clearly understood. We propose that Aβ affects apoE transcriptionally through the activation of the beta-adrenergic receptor (βAR), cAMP and the activator protein 2 (AP-2). To test this hypothesis it was first determined if the stimulation of apoE protein levels by Aβ was triggered by an upregulation of apoE mRNA, in contrast to changes in secretion or degradation. The results show a time-dependent increase in apoE mRNA expression levels with peak expression reached after 1 hour of Aβ treatment. βAR antagonists were used to evaluate the involvement of the βAR. The antagonists significantly inhibited the Aβ-induced stimulation of apoE mRNA and protein levels. In order to further understand the mechanism behind these results we assessed cAMP role in the proposed Aβ-apoE pathway. This second messenger has been associated with AD and has been shown to elevate apoE message and secretion levels. The data shows an Aβ-dependent elevation in cAMP levels as well as an increase in apoE levels after dBcAMP treatment, confirming the activation of a cAMP-dependent pathway. In addition, I provide evidence that confirms the participation of the transcription factor AP-2, specifically that of AP-2β. AP-2 is known to be unregulated by cAMP and to bind to the apoE promoter. I report an increase in AP-2β translocation to the nucleus after both cAMP and Aβ treatment and confirm its participation in the activation of the apoE promoter. In conclusion, my work reveals a novel pathway for Aβ stimulation of apoE abundance in astrocytes involving βAR and the transcription factor AP-2β. These findings not only help clarify the relationship between Aβ and apoE but also help understand AD progression and possibly show a mechanism that could aid in the fight against this fast growing disease.
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    Apolipoprotein E and Cognitive Impairment in PTSD: Assessing Genetic Risks and Protections
    (2021-11) Johnson, Rachel
    This study bridges gaps in the Posttraumatic Stress Disorder (PTSD) literature by providing a rigorous evaluation of the relationships between trauma exposure, PTSD symptoms, Apolipoprotein E (ApoE), and cognitive functioning. A total of 932 U.S. veterans (N=643 males) completed diagnostic interviews of mental health, a cognitive screener, self-reports of PTSD symptom severity and exposure to traumatic events, and blood tests to collect genetic information. Analysis demonstrated that veterans with PTSD perform worse than those without on the Montreal Cognitive Assessment (MoCA), regardless of comorbid depression, and that current PTSD symptoms and Pre-deployment exposure to potentially traumatic events are associated with lower performance on MoCA. Interestingly, veterans with PTSD and a comorbid depressive disorder had higher PTSD symptoms and exposure to potentially traumatic events (PTEs) than veterans with PTSD alone. Higher ApoE cysteine residues per mole were associated with lower PTSD symptoms, indicating its protective nature. Finally, structural equation modeling showed that higher cysteine residues per mole indirectly predicted higher cognition, through lowering PTSD symptoms that negatively affect cognitive functioning. These analyses provide new information regarding the complex relationships between trauma exposure, symptom severity, genetic susceptibility and cognitive function in the context of PTSD in U.S. veterans. Strategies to use these results to improve holistic clinical care and further valuable research include: recommendation for the use of MoCA as a screening tool for cognitive function and referral to other providers, consideration of the impact of Pre-deployment trauma exposure on both current PTSD symptoms and cognitive function, and clarification on the importance of assessing ApoE using cysteine residues per mole to fully interpret risk and protective factors. Finally, these results, taken together using structural equation modelling, illustrate the intricacy of relationships between the many factors contributing to an individual’s presentation with PTSD, an important reminder when working with those experiencing this difficult condition.
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    HDL-Mimetic Peptides as Potential Therapeutics for Alzheimer's Disease
    (2018-08) Chernick, Dustin
    Alzheimer’s disease (AD) is the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. A number of large scale human clinical studies have confirmed a robust connection between high density lipoprotein (HDL) – known as the ‘good cholesterol’ levels and AD. Low levels of HDL are associated with increased risk and severity of AD. The role of HDL in the brain is not fully established, however, the anti-inflammatory and anti-oxidative properties of HDL are thought to be critical for its beneficial effects. Apolipoprotein E (apoE) is a key constituent of HDL-like particles in the interstitial fluid (ISF) and cerebral spinal fluid (CSF) in the brain. ApoE exists in 3 common variants in the human population (apoE2, E3, and E4), and the apoE4 isoform is the strongest genetic risk factor for AD, accounting for 40-60% of cases. This risk allele is known to increase neuroinflammation and to promote the aggregation and deposition of amyloid beta (Aβ) in the brain, effects which are influenced by the poor lipidation status of apoE4 (incomplete or improper composition of HDL-like particles) in the brain. Previous studies in the laboratory of Dr. Ling Li have shown that overexpression of human apoA-I, the primary apolipoprotein associated with HDL in the periphery, mitigated amyloid pathology and rescued memory deficits in AD mice. However, a full-length, glycosylated protein is extremely difficult and costly to synthesize and to administer. Therefore, the goal of my research was to test the therapeutic potential of small HDL-mimetic peptides, designed to mimic the beneficial function of their parent apolipoproteins, in AD. My studies focused on 4F, an 18 amino acid HDL-mimetic peptide that has been shown to be safe and well tolerated in human clinical trials for cardiovascular disease. I have demonstrated that the lipidation state of apoE is negatively impacted by the addition of aggregated Aβ to astrocytes from mice and humans, in vitro, an effect that is reversed by the addition of 4F. In addition, I confirmed that apoE4 is less lipidated than apoE2 and E3 at baseline, and demonstrated that apoE4 is more susceptible to the detrimental effects of Aβ on lipidation than apoE2. Intriguingly, 4F was able to completely rescue this effect, bringing apoE4 lipidation levels on par with those of apoE2, even in the presence of Aβ. Preliminary in vivo studies in mice expressing the human apoE isoforms and in a mouse model of AD indicate that 4F reduces soluble amyloid levels in the brain and attenuates memory deficits. As chronic neuroinflammation is a key hallmark of AD pathology, another line of my research focused on a small molecule, called Minnelide. Minnelide is a water soluble, pro-drug of triptolide, which is an anti-inflammatory agent that has been shown in Dr. Li’s lab and in other labs to mitigate AD pathology and rescue memory deficits in animal models. Poor solubility hinders this agent’s prospects in the clinic, and so we sought to test the efficacy of Minnelide in AD. My studies show that Minnelide attenuated age-related cognitive decline in AD mice, independent of Aβ levels in the brains of these animals. These data, taken together, indicate that HDL mimetic peptides, and targeting of inflammatory pathways in the periphery and in the brain are promising avenues for continued efforts to find an effective treatment for AD.