Master of Fine Arts (MFA)
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Frank van Breukelen
Number of Pages
Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive impairments and pathological hallmarks that include amyloid plaques, neurofibrillary tangles, and neuronal loss. Several well-known mutations exist that lead to early-onset familial AD (fAD). However, these cases only account for a small percentage of total AD cases. The vast majority of AD cases are sporadic in origin (sAD) and are less clearly influenced by a single mutation but rather some combination of genetic and environmental risk.
The etiology of sAD remains unclear but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors, Type II Diabetes Mellitus (DM) and chronic inflammation of the brain have been implicated as two leading risk factors. Longitudinal studies have identified that patients with T2DM have nearly twice the risk of developing AD. DM is a common metabolic disorder that affects a quarter of the elderly population with symptoms that include insulin dysregulation and altered glucose metabolism. Numerous studies link insulin resistance in the brain with an increased risk of AD. Intracerebroventricular (ICV) administration of the diabetogenic drug streptozotocin (STZ) leads to brain insulin resistance and several AD-like pathologies including progressive deterioration of memory, increased Aβ load and hyperphosphorylated tau. STZ has been proposed to be a relevant animal model of sAD.
Additionally, neuroinflammation has been implicated in playing a fundamental role in the progression of the neuropathological changes observed in AD brains. Neuroinflammation is typically thought to be a result of one or more of the other AD pathologies and serves to rapidly progress the disease. Lipopolysaccharide (LPS) is capable of mounting an immune response through the activation of Toll-like receptor 4 (TLR4). Studies involving transgenic models routinely activate the immune system by administering LPS to exacerbate AD-like deficits to better understand the role of neuroinflammation in AD.
The majority of AD models rely on genetic mutations and provide valuable information regarding the role of Aβ and tau pathologies but do not represent the prevailing sAD. Considerable research has been conducted to help elucidate the risk factors associated with sAD, including DM and neuroinflammation. However, there is a lack of research regarding the role of neuroinflammation in this particular model of sAD. The purpose of this study was to investigate the effects of a one-time immune activation in the STZ model on learning and memory and proteins associated both with AD hallmarks and with various neurotransmitter systems. Results indicated that an acute inflammatory response played a beneficial role in spatial learning and in several of the investigated proteins. These data may help shed light on the role of brain inflammation in AD.
Alzheimer's disease; Alzheimer's disease – Risk factors; Diabetes; Diabetes mellitus; Insulin resistance; Insulin signaling; Lipopolysaccharide; Neuroinflammation; Non-insulin-dependent diabetes; Streptozotocin
Biological Psychology | Medical Neurobiology | Neuroscience and Neurobiology | Neurosciences | Psychology
Murtishaw, Andrew Scott, "The Effect of Acute LPS-Induced Immune Activation and Brain Insulin Signaling Disruption in a Diabetic Model of Alzheimer's Disease" (2014). UNLV Theses, Dissertations, Professional Papers, and Capstones. 2199.