Alzheimer’s disease (AD) is a neurodegenerative disorder that disrupts memory, thinking, and behavior. It is the most common type of dementia and occurs with increasing frequency with increasing age. Transgenic AD mouse models have not predicted clinical efficacy because neurodegeneration occurs rapidly at a young age, so an aging environment is not a factor. To address this, an adeno-associated viral vector model of AD (AAV-AD) containing a green fluorescent-induction marker (GFP) was created to deliver pathogenic proteins Aβ-42 and P301L tau to neurons of old mice. The AAV capsid was engineered to have an affinity for neurons. Analysis of the model demonstrated successful expression of Aβ-42 and P301L tau in neurons in the brains of old mice when the vector constructs were administered intravenously (IV). However, it has yet to be shown whether the AAV-AD vector has off-target effects in systemic organs like the liver. Characteristic AD pathology does not naturally occur outside the brain. Therefore, this project was designed to determine if the AAV-AD vector became established in hepatic cells. Paraffin-embedded tissues were obtained from 27-month-old C57BL/6 male and female mice infected with the AAV-AD or sham vector for 3 months. Immunohistochemistry (IHC) was used to examine expression of GFP, Aβ-42, P301L tau, MCP-1 inflammatory cytokine, and yH2AX DNA-damage response. Images were taken using digital microscope software, and quantified through an open-source digital image software. Age-related histopathology lesion scores from H&E-stained brain and liver were compared with IHC stains. The expectation is there will be little evidence of AAV-AD proteins but incremental increases in inflammatory and DNA-damage proteins proportional to histopathology lesion scores. These observations would help validate translational efficacy of the AAV-AD mouse model for preclinical testing of pharmaceuticals to treat or prevent AD.

Sleep deprivation (SD) is a pervasive issue linked to significant cognitive and neurological impairments, affecting billions of people. SD accelerates markers of aging, but some individuals exhibit resilience to its effects. SD response is indicative of resilience. Identifying factors that promote SD resilience may inform interventions to enhance resilience. Studies have shown that SD alters gene expression in rodents, yet it remains uncertain which changes are specific to homeostasis. Previous rodent studies examined the effects of single day SD. Our study increases the duration to five days and separates mice into high and low responders, providing a novel insight into SD responses. This establishes a valuable evaluation of resilience for aging interventions. Female mice in the treatment group were sleep deprived through continuously stirring them during sleep periods. Control and treated mice were then subjected to the box-maze assay to evaluate relative learning rates and cognitive impairment. High performance in the box maze was designated as a high responder, and vice versa. Mice were then euthanized, and the hippocampus was isolated. The transcriptomes of control and treated mice were analyzed via mRNA sequencing. Analyzing transcriptomes of control, high, and low responder mice showed distinct changes in expression of key physiological and biochemical phenotypes. Genes known to be associated with SD were isolated and examined separately regardless of difference. Overall, high degrees of similarity were observed in control and high responders to SD, while low responders had the greatest changes in comparison to the latter groups. These experiments provide an efficient, robust platform to study the biochemical effects of SD, offering attractive insights for frameworks to quickly evaluate therapeutic strategies aimed at enhancing resilience to aging,