The Role of Interstitial Fluid Flow in the Progression of Glioblastoma and Alzheimer's Disease

The human brain is a complex organ that is responsible for regulating all the physiological processes in the body, ranging from memory to movement. As humans age, the brain goes through a variety of changes including a reduction in glymphatic waste clearance and increase in glial reactivity. Two neurological conditions that affect individuals over the age of 65 include glioblastoma (GBM) and Alzheimer's disease (AD). Interestingly, patients with GBM do not present with AD and vice versa. Both conditions are characterized by a disruption in interstitial fluid flow (IFF) and an increase in neuroinflammation. Throughout the following dissertation, we examined the role of IFF in AD and GBM progression using a three-sided approach (in vivo, in vitro, and in silico). Increased IFF underlies glioma invasion into the surrounding tumor microenvironment (TME) in GBM. We used a 3D hydrogel model of the GBM TME to examine potential pathways by which astrocytes and microglia contribute to glioma invasion. A reduction in IFF contributes to accumulation of the toxic protein amyloid beta (Aβ) in AD. We sought to create a novel, patient-inspired model of the AD hippocampus for examination of the relationship between IFF and Aβ clearance. Human AD and unaffected control hippocampal brain samples were stained for markers of neurons, astrocytes, microglia and Aβ. The percentage of each cell population in the CA1 region of the hippocampus was calculated. We also analyzed the amount and characteristics of the Aβ aggregates present in this hippocampal region. Pearson correlation analysis was completed to assess the relationships between the various cell populations, Aβ load, and patient descriptors. The cell ratios gleaned from the patient samples were incorporated into a novel, 3D hydrogel model of the AD hippocampus. This model features a hydrogel mixture like the native brain extracellular matrix (ECM) and allows for the application of IFF and Aβ. To our knowledge, we are the first group to create a patient-specific triculture model of the AD hippocampus, which is the main site of Aβ aggregation in the AD brain. We used this model to examine the relationship between IFF-mediated Aβ clearance and glial reactivity. The last aim of this dissertation was to create a computational model for examining Aβ binding within the ECM and the effects of IFF on Aβ clearance. In vitro experiments were conducted to generate 3D renderings of glial cells and to determine relevant parameters for our model. Throughout this work, we discuss the relationship between disruption in IFF and glial reactivity in the context of GBM and AD.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biomedical Engineering

Department dc:contributor.department

Department of Biomedical Engineering and Mechanics

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2022

Author dc:creator

• Tate, Kinsley

Chair dc:contributor.committeechair

• Munson, Jennifer M.

Committee members dc:contributor.committeemember

• Kimbrough, Ian
• VandeVord, Pamela J.
• Olsen, Michelle Lynne
• Theus, Michelle H.

• interstitial fluid flow
• glioblastoma
• Alzheimer's disease
• glial reactivity
• cell model development

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:35929

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/112754