Podium Session A

ABSTRACT:

Introduction: Insulin dysregulation and resistance participate in the etiology of Alzheimer disease (AD) pathologies, however, little is known about the possible correlation between diabetes and the progression of cognitive decline in patients. Previous studies have shown an increased risk of developing AD in patients with type 2 diabetes mellitus (T2DM). Our study aims to determine whether differences exist in cognitive decline experienced by AD subjects with and without T2DM co-morbidity.

Methods: : Cognitive performance data and the presence of T2DM co-morbidity in AD patients were derived from the Uniform Data Set (UDS) of the database maintained by the National Alzheimer’s Coordinating Center (NACC). The UDS database identified 3055 participants with AD who had more than one epoch completed. These patients were divided into two groups dependent upon the presence of a diagnosis of T2DM. The data from these groups was then analyzed for differences in cognitive decline based upon Neuropsychological Battery Scores and a Clinician Dementia Rating (CDR) using a general linear model.

Results: Cognitive function tests looked at language, cognitive executive function, and verbal and nonverbal memory. Comparison of the mean scores in 16 selected tests showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and non-diabetic groups.

Discussion: It was found that there were no differences in cognitive decline metrics over the course of 5 visits in either group. This supports the position that the presence of T2DM does not appear to increase the magnitude of cognitive decline in AD patients.

ABSTRACT:

Glycogen synthase kinase 3β (GSK3β) is one of the primary kinases that cause the formation of amyloid plaques and neurofibrillary tangles, which are the hallmark pathologies of Alzheimer’s disease. Therefore, GSK3β is a vital therapeutic target. However, GSK3β is also a versatile kinase involved in multiple cellular signaling pathways. Therefore, our study aims to identify a pathway-specific inhibitory site(s) on the GSK3β structure by analyzing the binding interaction between Beryllium ion (Be²⁺) and model peptides designed to mimic potential binding pockets. Be²⁺ is a potent inhibitor of GSK3β activity and has shown evidence suggesting a pathway-specific inhibitory mechanism. The GSK3β structure has several sites containing amino acids with carboxylate groups Asp (D) and Glu (E), potentially binding with positively charged compounds. For example, Magnesium ion (Mg²⁺) binds with GSK3β residues Asp200 and Asp264 to activate it. We compared the binding of Be²⁺ and Mg²⁺ with carboxylate-rich model peptides by using isothermal titration calorimetry and microscale thermophoresis. The binding analysis followed Be²⁺ and Mg²⁺ with peptides DDDD, DDDG, DGDG, and EEEE displayed binding with Be²⁺ but not with Mg²⁺. Be²⁺ did not bind with the model peptide GGDD. The number of binding sites for Be²⁺ on the peptides DDDD, DDDG, DGDG, and GGDD was 2, 1, 1, and 0. Additionally, Be²⁺ bound weakly with EEEE peptide compared to DDDD. These results indicate that the potential Be²⁺ binding site on GSK3β would have two alternatively spaced Asp acid residues in a fixed binding pocket independent of Mg²⁺ binding sites.

ABSTRACT:

Reactive oxygen and nitrogen species (ROS/RNS) such as hydrogen peroxide (H2O2) are typical byproducts of oxygen metabolism and can lead to oxidative stress when produced in large amounts. This is a concern since oxidative stress can cause neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and some forms of cancer. While there are several modes of detection of ROS/RNS like H2O2, electrochemical methods offer several advantages: low cost, capability to be miniaturized, and rapid detection. With respect to the electrodes, carbon-based materials are particularly useful due to their ability to be adapted to different measurement scenarios. For H2O2, carbon-fiber microelectrodes are most common but tend to foul with long-term exposure to an oxidative environment. Boron-doped diamond (BDD) can mitigate this issue due to its general robustness; it also exhibits a small capacitive current, enhanced surface roughness, and a large potential window. BDD can also be modified to increase sensitivity towards a specific analyte, like H2O2. In this work, we performed a comprehensive study of BDD electrodes modified with silver (Ag), gold (Au), palladium (Pd), and platinum (Pt) nanoparticles for the detection of H2O2. The modification involves a 2-step wet chemical synthesis procedure directly onto the electrode surface. Several factors were investigated including the double-layer capacitance, electroactive surface area, electron transfer properties, and sensitivity to H2O2, among others. It was found that the modification yielded a 1x (Ag), 1.1x (Au), 184x (Pd), and 178x (Pt) increase in sensitivity compared to the bare BDD electrode. The best combination of analytical figures of merit was observed with Pd where the limit of detection (LOD) was calculated to be 0.02 µM. The H2O2 measurements also exhibited excellent repeatability as the relative standard deviation (%RSD) was below 10% for all modifications. In general, this work further exemplifies the versatility of diamond electrode for detection of bioanalytes.

ABSTRACT:

Folate is an essential B vitamin naturally found in the human diet that plays a key role in deoxyribose nucleic acid (DNA) methylation. Alterations to the DNA methylation pathway contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer’s Disease (AD). The AD population tends to have higher rates of folate deficiency than the general geriatric population. We questioned whether folate deficiency had a greater effect on DNA methylation levels in an AD population compared to a healthy population. To test this, mice were divided into two groups. One group was injected with DSP4, a neurotoxin that simulates neurodegeneration seen in AD, and the other group served as an unadulterated control. Each of these groups were further divided into 3 subgroups, yielding a total of 6 groups, and fed either a folic acid deficient, sufficient, or excessive diet for 8 weeks. Our results dictated that there were group differences in DNA methylation between the diet groups (p<0.05). Within the AD population, DNA methylation was 145% higher in the folate deficient group compared to the control diet. However, within the control group, DNA methylation was 51% lower in the folate deficient group compared to the control diet. This indicates that the folate metabolism and DNA methylation pathway in AD may be altered, contributing to neurodegeneration by decreasing overall gene expression. Based on our results, further examination into the relationship between folate intake and DNA methylation within neurodegenerative disease states, such as AD, is warranted.

ABSTRACT:

Diabetes mellitus (DM) is associated with dysregulated glucose and insulin levels. Over 37 million Americans have been diagnosed with DM, most of who have type 2 diabetes (DM2). Individuals with DM2 exhibit mild cognitive impairment and are more likely to develop Alzheimer’s disease (AD) later in life. While the relationship between DM2 and AD is still unclear, evidence suggests that elevated blood glucose (BG) levels lead to neuroinflammation and contribute to tau hyperphosphorylation in the brain. Indeed, animal models of DM2 exhibit hypersynchrony between brain areas, which is also common in the early stages of AD, but it is unknown whether these changes occur because of elevated BG levels. We designed a within-subject experiment utilizing streptozotocin (STZ) injections to induce sustained elevations in BG levels and phloridzin, a drug known to cause decreases in BG during long-term in vivo recordings of brain activity of rodents. Subjects were trained on a conditioned place preference task to measure contextual memory recall and varying BG levels over one to 130 days. Preliminary data suggest that contextual memory recall performance and neural activity differ from baseline performance in animals with decreased or elevated BG levels. Interestingly, behavioral performance improved in subjects who received STZ and phloridzin injections, suggesting a relationship between BG and cognitive ability. Together these findings show that animals with low or high BG levels exhibit striking changes in network activity in the hippocampus. This work could yield exciting results to help explain the relationship between DM2 and AD.