Alzheimer’s disease (AD) is ranked as the seventh leading cause of death in the US with over 6 million Americans currently diagnosed, and that number is projected to reach about 13 million by 2050. AD is currently believed to be caused by numerous factors ranging from genetics, lifestyle, and environmental conditions. The exact pathogenesis of AD remains uncertain, but the pathology of the disease includes the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles composed of the protein tau in the brain. These are two proteins are normally found in the brains of healthy individuals, but amyloid-beta peptides are often degraded under normal conditions, while tau plays a role in stabilizing our cell’s cytoskeletal structures. In Alzheimer’s however, these proteins are misfolded and accumulate, causing disruptions in cell signaling and neuronal death, therefore worsening the disease. Aβ plaques also activate microglial cells, which produce cytokines and induce inflammation. Cytokines are signaling molecules produced by immune cells that mediate inflammatory signaling. Activation of an inflammasome complex found in microglial cells, NLRP3, leads to the production of the cytokine IL-1β which has been implicated in Alzheimer’s due to its ability to induce and maintain this chronic cycle of inflammation, and possibly results in more amyloid-beta deposition. Our research looks into the mode of action of novel anti-inflammatory drugs and their potential to reduce inflammation at the level of the NLRP3 inflammasome as a mechanism to slow down the progression of AD.
 

Alzheimer’s disease is the most common form of dementia and affects over 6 million Americans 65 and older. In the absence of a cure, addressing modifiable risk factors could potentially reduce the risk of AD development. There is an established relationship between diet and AD risk. For example, studies in rodents found that highly processed Western diets are associated with cognitive impairment and increased amyloid-beta in the hippocampus, a brain region critical for learning and memory. Conversely, plant-based diets like the Mediterranean diet (MD) have been shown to protect against cognitive impairment.

A key limitation in the scientific literature is that most animal studies have only examined the effects of extremely high-fat WD (providing over 40-60% kcal from fat), or a MD with only one or two key nutritional components. We aimed to fill a gap in the literature by designing a rodent diet that mimicked the typical American diet (TAD), rather than an exaggerated WD, and a macronutrient-matched MD. C57BL/6J mice were weaned onto one of the two diets at postnatal day 21. Following six months of diet, we conducted behavioral tests, including open field, elevated zero, and object-location memory task (OLMT). In comparison to the MD, mice consuming the TAD had decreased locomotor activity and exploratory behavior, increased anxiety-like behavior, and reduced spatial memory.

Mercury contamination is of increasing concern. As the earth’s temperature continues to rise, it is vital to study the trends of MeHg absorption. Continuing to gather MeHg absorption data in the Northwest part of Greenland will help to grow our understanding of MeHg trends in Arctic territories. This study will increase the amount of data collected on MeHg levels, allowing a more accurate comparison between MeHg level patterns and species behavior, breeding success, and death rates in Arctic bird species (Chastel et al., 2022). Understanding how MeHg contamination affects health and prosperity is critical, not only for the environment and animals but people as well, as these birds are often part of the native Greenlander diet (Hong et al. 2012; Johansen et al. 2004). Temporal monitoring is also highly beneficial for evaluating the efficacy of policies aiming to reduce anthropogenic Hg emissions (AMAP 2021).

Pyridinophane molecules have recently been shown to have both antioxidant and pharmacological properties suitable for therapeutic applications targeting neurodegenerative diseases, including Alzheimer’s Disease. We have synthesized derivatives of this parent molecule with added moiety substitutions. These substitutions are designed to enhance the permeability and antioxidant activity beyond that of the parent molecule in the hopes of producing a molecule suitable for pharmacological testing in animal models. To establish a principle between moiety location on the parent molecule and its activity, we have placed 8-hydroxyquinoline, a moiety established in our lab to improve the antioxidant activity of parent molecules, in varying locations. The results presented here will detail our evaluation of the substitution of 8-hydroxyquinoline in varying locations and its impact on the molecule’s permeability and reactivity through a series of statistics, including a DPPH assay, determination of logBB, and the determination of chelating equilibrium quotients at varying pH (“log beta”).

Alzheimer’s Disease (AD) affects over 6.5 million Americans over the age of 65. Previous research links AD with Amyloid-Beta-40 (AB40) aggregation in the brain, which creates neurotoxic plaques, associated with AD. A potential mechanism in the treatment of AD is using therapeutics that will prevent the formation of these plaques, which is possible with Metal Chelation Therapy.
Metal ion chelation ideally stops metal ions from aiding in the aggregation of AB40. However, to deliver metal chelating agents to the brain, a drug-delivery mechanism is required that will be able to deliver this medicine across the Blood-Brain Barrier. Porous silica is a potential drug delivery material due to its small particle size, high loading capacity, surface tunability, and biocompatibility. Along with these characteristics, porous silica can create a “sustained” release of a given drug, allowing for a slow and steady release profile, reducing the risks of medication side effects.
This project seeks to establish the optimal loading capacities of a class of potential metal ion chelate therapeutic molecules known as pyclens into porous silica, each with different pyridyl moieties and chemical functionalities along the rim of the molecule. Encapsulation efficiencies measurements for these pyclen derivatives reveal loading percentages in the 10-19% range, varying by pyclen identity. Additionally, release studies monitored diffusion over time to find which pyclen molecule achieved “sustained” release. All loaded pyclen species were able to show sustained release after 20 minutes, both in the presence and absence of copper (II) ions. Turbidity assays with AB40 present showed that all pyclen species decreased protein aggregation in the presence of copper (relative to non-pyclen controls), showing that all pyclen species were able to successfully prevent the aggregation of AB40 in the presence of copper.
Release studies in a more authentic BBB model remain to be completed.