Alzheimer's disease (AD) is the most common form of dementia and results in progressive cognitive decline, particularly in regards to memory (National Institute on Aging, 2012). Prior research has shown sex differences in brain-atrophy rates of AD patients, with women experiencing a higher rate of progression in volume reduction (Skup et al., 2011). This suggests that there may also be differences in cognitive functioning between sexes, particularly in the rate of cognitive decline with a more rapid disease progression for dementing females compared to dementing males. The current study monitored memory function longitudinally in approximately 200 total participants, 100 with Mild Cognitive Impairment (MCI) or probable AD and 100 healthy controls enrolled in an aging study through the Arizona Alzheimer's Disease Research Consortium. Memory performance was evaluated with two memory tests, the Rey Auditory Verbal Learning Test (RAVLT; Rey, 1941) and the Brief Visuospatial Memory Test-Revised (BVMT-R; Benedict, 1997). Memory function was evaluated in participants with at least three data points over a five-year span. A multivariate regression model was used that includes controls for disease severity, age, age at disease onset, education, ethnicity, and medical comorbidities. Results indicated that females in the MCI and AD groups initially performed better than the males, but that over time, female scores had dropped significantly lower than male scores, suggesting a more rapid decline in females. Significant sex differences in cognitive decline may yield a deeper understanding of the development and progression of AD and aid in more effective and sex-specific treatment.

The prevalence of both Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing worldwide, and the trends are unfortunately expected to continue. AD has recently been tied with mitochondrial dysfunction and insulin resistance, creating a mechanistic tie between AD and T2DM. Unfortunately, insulin resistance is often increased with aging and therefore, all individuals are at risk of brain mitochondrial dysfunction. Without proper mitochondrial function, the brain will degenerate, causing impaired cognitive function and reduced quality of life. The purpose of this study is two-fold: first, to understand the role of ceramides in insulin-induced brain mitochondrial dysfunction, and; second, to understand how ketones can restore brain mitochondrial function in aged brains. To evaluate the role of insulin resistance and ceramides in brain mitochondrial function, we induced hyperinsulinemia in ApoE4 mice. In addition to insulin, one group received myriocin injections to inhibit ceramide biosynthesis. We observed significant increases in brain ceramides in the insulin-treated group, which correlated with disrupted brain mitochondrial function. However, the group receiving myriocin alone, and, importantly, myriocin with insulin, had normal lipid profiles and normal mitochondrial bioenergetics. Altogether, these findings support the hypothesis of the key role of ceramides in insulin resistance-induced mitochondrial dysfunction within the brain. Next, young adult (5 months old) and old (28 months old) rats were assigned to either standard chow diets or very-low-carbohydrate, high-fat, ketogenic diets for 4 weeks. Following the treatment period, we analyzed brain mitochondrial function and oxidative stress. We found that the old rats fed the ketogenic diet had improved mitochondrial function in comparison to the old rats consuming standard rodent chow. In addition, the old rats fed a standard diet had significantly higher levels of oxidative stress than the aged rats on the very-low-carbohydrate, high-fat diet. These findings revealed that ketones can protect brain mitochondrial function in aging. Collectively, these results suggest that insulin resistance has a role in the development of brain mitochondrial dysfunction due to ceramide accumulation, while ketones can help mitigate some of the negative consequences of aging, perhaps some due to insulin resistance, on brain mitochondrial function.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of peoples’ lives worldwide. While the consequences of AD are recognizable, the etiology is unclear. Gene-environment interactions have been implicated in the development of the disease, and exposure to organophosphorus (OPs) compounds is one of the environmental factors associated with AD. Evidence links exposure to levels of OPs encountered in agriculture, horticulture, and other work places with neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Unfortunately, the mechanisms underlying these effects have yet to be established. Here, we set out to examine the long-term consequences of exposure to a commonly applied OP insecticide, chlorpyrifos (CPF), in an attempt to identify a causal link between occupational exposures and chronic illnesses. We exposed a transgenic rodent model of AD, TgF344-AD, to levels of CPF representing occupational exposures and examined ensuing behaviors and neuropathologies. We observed a sex-specific, biphasic response in CPF-exposed animals, including acute neurotoxicities, followed by intermediate recovery, and finally, chronic cognitive impairments. CPF exposure exacerbated neuronal damage in brain regions critical to the impaired behaviors, and neuroinflammatory pathways were identified as facilitators of this damage. This work emphasizes the long-term consequences of early life repeated exposures to OPs and identifies dysregulated microglia as a potential deleterious modifier of disease. Additionally, we investigated the efficacy of a neuroprotective compound, (-)-P7C3-S243 in TgF344-AD rats. P7C3 compounds exert protection by preventing young hippocampal neurons from dying prematurely and also enhancing flux of nicotinamide adenine dinucleotide (NAD), thereby aiding in neuron survival under conditions that normally cause axon degeneration and cell death. These compounds have proven effective in preclinical models of Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. Thus, we sought to investigate the neuroprotective efficacy of P7C3 compounds in AD, as well. (-)-P7C3-S243 was administered to wild-type and transgenic male and female rats daily for 9 and 18 months, and classic hallmarks of the disease were assessed. Transgenic rats developed a spectrum of AD pathologies and behaviors, as expected, and (-)-P7C3-S243 ameliorated early depression-like behaviors, late learning and memory deficits, and progressive neuronal damage in this model, without influencing amyloid plaque deposition, tauopathies, or neuroinflammation. This data suggests that targeting neuronal cell death pathways is a promising treatment strategy in AD. Taken together, the research presented here expands our current understanding of pathways of regulation in Alzheimer’s disease—organophosphates are capable of exacerbating the severity of AD, while P7C3 compounds are promising therapeutic candidates for neuronal death in the disease. Given the overlapping molecular pathways of modulation in CPF-induced toxicity and (-)-P7C3-S243 neuroprotection in AD, future studies will investigate the efficacy of (-)-P7C3-S243 in cognitive deficits induced by CPF exposure. Ultimately, this body of work highlights the plasticity of neuronal cell death and cognitive impairment in AD, thus indicating a better understanding of these pathways could facilitate vastly improved intervention strategies in Alzheimer’s disease.

Mechanobiology is an emerging field that aims to understand how physical forces regulate cell function, morphology, and development. Cells interpret forces, such as the deformation of the membrane to encapsulate a particle, or the rigidity of the extracellular matrix (ECM), and make decisions about cell adhesion, motility, and differentiation. These cell-ECM interactions are important to maintaining homeostasis, and the disruption of this interface has pathological consequences. Common diseases, such as Alzheimer’s disease, cancer, and atherosclerosis each arise, in part, from an abnormality in the mechanotransduction pathway. Hence, understanding the contribution of this pathway and the role of the ECM in cell function, proves to be a useful tool in improving drug targeting and understanding disease progression. While size, shape and surface chemistry of nanoparticle uptake has been extensively studied, varying the particle mechanics can also be a useful design strategy to manipulate particles and improve uptake and targeting. Using model polystyrene-co-N-isopropylacrylamide (pS-co-NIPAM) particles, with varying elastic moduli, it was observed that as the particles became stiffer, there was a subsequent decrease in bound/internalized particles for phagocytic RAW264.7 macrophage and non-phagocytic HepG2 hepatoma carcinoma cells, showing that both of these cell types are sensitive to particle mechanics, even in a higher stiffness regime (MPa). ECM mechanics have recently been implicated in tissue stiffness changes that precede and drive disease development. Recent research has started looking into these effects in the progression of neurodegenerative diseases. This research found that the elasticity of the brain becomes softer with aging, and even softer in patients with AD. Analogous to the pS-co-NIPAM studies, this tissue softening could have implications on amyloid-beta endocytosis as well as neuron dystrophy in response to the peptide. Understanding the role of the ECM in the progression of AD in vitro could provide a better approach to determine an in vivo mechanism behind Alzheimer’s disease pathology. In order to mimic a softer ECM substrate, SH-SY5Y neuroblastoma and human primary neurons were plated on 2-D polyacrylamide and 3-D collagen gels with varying stiffness ranging from 0.15-25kPa. Both cell types grown using these substrates show a sensitivity to their ECM environment, and display an increase in cell spreading and the number of F-actin stress fibers with an increase in substrate rigidity. Moreover, the extent of Aβ internalization and aggregate production increased with ECM stiffness for SH-SY5Y neuroblastoma. Intracellular Aβ processing remains a central question to understanding the early-stage events in AD pathogenesis. As the ECM can modify Aβ endocytosis and aggregation, the ECM is likely influencing downstream neurotoxic effects of AD. Despite an increase in the plaque production on the soft substrates, both SH-SY5Y neuroblastoma and primary neurons showed a decreased toxicity to Aβ with decreasing substrate stiffness. This decrease in toxicity is associated with cytoskeletal actin remodeling, as cells plated on plastic, but pretreated with cytochalasin D displayed a recovery in viability in response to the oligomeric species. The softening of the ECM initiates actin cytoskeletal depolymerization, as a protective mechanism against neuronal loss and AD progression. This work demonstrates that the ECM impacts Aβ endocytosis and aggregation, and the ECM prompts neuroprotective actin reorganization against the neurotoxic effects of AD. Further, it is demonstrated the biophysical role of ECM stiffness in modifying Aβ internalization, plaque production, and toxicity offers an improved in vitro model of critical AD components. By better understanding the cytoskeletal reorganization triggered by a softening ECM, potential novel avenues of therapeutic intervention could later be determined to stop the progression of the disease.

Alzheimer's disease (AD) has multiple factors that contribute to the disease process. Among these is a state of chronic inflammation that is endured by the brain during the aging process. The use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the amount of neuroinflammation sustained by the brain, and greater levels of NSAID use have been demonstrated to be associated with decreased probability of developing AD. This study looked at whether greater rates of NSAID use were also associated with decreased rates of cognitive and funtional decline and survival in a population-based sample of persons with AD.

Alzheimer’s disease (AD), identified over 100 years ago and intensively studied since the 1970s, has no effective treatments or mechanistic understanding of the underlying neurodegenerative process. Most investigators believe accumulation or aggregation of amyloid beta (Ab) proteins plays a causative role. Aβ peptides (~39-43 residues) are generated by proteolysis of the transmembrane protein APP. One reason we know so little about AD is an incomplete understanding of the cellular mechanisms responsible for Ab proteotoxicity. Human ES and iPSC models of AD are recent additions to many other models used to investigate these mechanisms. AD, however is a chronic progressive condition of old age and cultured neurons may not live long enough to model what goes wrong in neurons from AD patients. In my research, I used hESCs which directly express Ab peptides thus avoiding the time it takes to process APP. One App allele in H9 hESCs was previously edited using TALEN. A homologous recombination cassette coding directly for a secretory form of either Ab1-42 or Ab1-40 and containing a stop codon, was inserted into the first exon of App upstream of the normal translational start site. I used multiple independently isolated clones of edited cells with 3 genotypes: App/App (unedited), App/Aβ1-40 and App/Aβ1-42. Expression of Ab from edited alleles was confirmed by qRT-PCR using primers specific for the edit. I first sought to establish if editing changed any aspects of neuronal differentiation in culture. All 3 genotypes have similar embryoid body (EB) development, and similar numbers and sizes of neuronal clusters (NC) up to 34 days after EB dissociation and neural differentiation. Immunostaining of neuronal markers, NeuN and DCX (doublecortin), likewise revealed no difference among edited and unedited cells, suggesting that the edits do not affect the ability of my stem cells to differentiate into neurons. I next measured accumulation of aggregated Ab using an aggregate specific antibody, 7A1a. Data at 34-days post EB dissociation indicates NCs in the Aβ1-42 edited cells accumulate significantly more aggregates relative to either unedited or Ab1-40 edited lines, a result consistent with the increased ability for Ab1-42 to form aggregates. Aβ aggregates also appear to be concentrated around fragmented nuclei within neuronal clusters suggesting that intracellular accumulation may play a key role in proteotoxicity. Additionally, I observed a significant decrease in the number of synapsin1 puncta, a marker of synapses, another feature of AD. I documented a nearly 3-fold greater neuronal cell death in both the Aβ1-40 and Aβ1-42 neurons at 70 days after differentiation. RNA sequencing data also shows independently isolated clones group together and show differential expression of genes related to memory and neuronal cell death. The early presence of Aβaggregation and subsequent cell death is in line with the chronic and progressive nature of AD and this is the first known model to exhibit a neurodegenerative phenotype. These isogenic cell lines thus appear to be useful to screen for therapeutics that may prevent or slow Ab1-42 dependent neurodegeneration and a tool to investigate Ab-dependent mechanisms with relevance to AD.

The purpose of this research was to explore the gender differences in caregiver burden in Alzheimer’s patients in the Inland Empire. Currently, there are more than half a million Californians who live with Alzheimer’s disease (Ross, Brennan, Nazareno, & Fox, 2009) and this number is expected to double over the next few years. Due to an increase in the older population and the rise of informal caregivers, the study provided insight as to how males and females perceive caregiver burden and how each gender responds to caregiver burden. This exploratory study utilized a quantitative research design through the use of questionnaires which measured caregiver burden through the use of the Zarit Burden Interview. A total of 38 participants were recruited through support groups at the Inland Caregiver Resource Center. Though findings did not suggest a gender difference in caregiver burden, they did indicate that there was a relationship between ethnicity and gender in relation to the caregiver and care receiver relationship. Implications for social work practice include assessment for and aid in the development of gender appropriate resources for informal caregivers of Alzheimer’s patients.

The purpose of this study was to investigate the reading comprehension abilities of those with mild and moderate dementia of the Alzheimer's type (DAT) and compare their performance to that of a sample of non-demented elderly. Thirty-eight male subjects were used, 20 non-demented elderly, nine mild DAT and nine moderate DAT. All were administered level B of the NRST. This test contains questions requiring three levels of inference: literal, translational, and high-level inference.

Reversible adenosine methylation (N6-methylation; m6A) at the RNA level was described in connection to the regulation of RNA fate. The N6-methyladenosine pathway is important for cognitive function and mechanisms related to memory, including the regulation of adult neurogenesis and synaptic plasticity. The objective of this study was to test the hypothesis that a decreased activity of the RNA-demethylase FTO is associated with improved cognitive function in rats. The RNA-demethylase FTO is a key regulator of the m6A pathway. In this study, we administered MO-I-500, a pharmacological inhibitor of FTO in TgF344-AD transgenic rats, which resulted in an improvement of spatial cognition. We further investigated the cognitive enhancement induced by a caloric restriction as a possible compensatory mechanism of cognitive disorders and its effect on the proteins regulating the N6-methyladenosine pathway. Long-term caloric restriction ameliorated cognitive functions and led to changes in the expression of the major proteins controlling the m6A pathway (FTO, METTL3) which are consistent with the aforementioned hypothesis. Although we do not know the exact mechanism of action, these findings support the hypothesis that m6A pathway regulators, such as the FTO demethylase, may be a promising molecular target for...