The contribution of dynamic neuroinflammatory states in Alzheimer’s disease
Open Access
- Author:
- Kuhn, Madison
- Graduate Program:
- Biomedical Engineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 06, 2023
- Committee Members:
- Elizabeth Proctor, Chair & Dissertation Advisor
Xiaojun Lian, Major Field Member
James Connor, Outside Field Member
Bruce Gluckman, Outside Unit Member
Irina Elcheva, Outside Field Member
Justin Pritchard, Major Field Member
Yuguo Lei, Professor in Charge/Director of Graduate Studies - Keywords:
- Systems Biology
Alzheimer's Disease
Neuroinflammation
Immunometabolism
Cytokine Signaling
Cerebral Organoids - Abstract:
- It is well appreciated that neuroinflammation is a driver of Alzheimer’s disease (AD) pathology, but its complex contribution has been difficult to untangle. Immune activation, particularly by microglia, is needed to restore brain homeostasis, but under chronic immune insult, immune signaling becomes dysregulated in a variety of ways. The diverse collection of cellular immune activation states that underly the overall neuroinflammatory milieu of the brain uniquely contributes to pathology spread and the vulnerability of neurons. Contradictory activation states, such as an under-reactive response with loss of beneficial function and a detrimental, overreactive one, complicate efforts to restore beneficial function, both in the identification of therapeutic targets and treatment timelines. This dissertation was designed to dissect the contribution of the brain’s dynamic neuroinflammatory state from different levels of view. I first used an AD mouse model for tissue-level characterization of dysregulated immune cues to identify how diverse immune states collectively present in progressing disease and converge to affect neuron health. I identified a disease-predictive cytokine signature that, when applied to healthy neurons in the absence of pathology, reduced neuronal mitochondrial respiration, supporting the existence of pathology-independent neuroinflammatory effects on neuronal vulnerability. I then applied an AD cerebral organoid model to dissect microglia-specific function related to the immune milieu and its corresponding changes in pathology. AD organoids derived from human iPSCs carrying the N141I PSEN2 mutation from a male or female individual exhibit drastically different cytokine signatures and a different evolution of those signatures with age. The male organoids demonstrated an overall reduction in cytokine secretion after an initial amplified immune response, while female organoids showed a persistent heightened immune response. There was reduced synapse density in the male organoids, whereas larger deposition of amyloid and tissue atrophy occurred in the female organoids. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins and may represent early events in disease. Cumulatively, these studies achieved a quantitative characterization of the overall immune milieu, made up of a diverse of collection of activation patterns and immune responses, that is sufficient to negatively impact neuronal health and identified cell-specific contribution of microglia.