Alzheimer’s Disease Risk Conveyed by Apolipoprotein E ε4: Immunometabolism and the Brain-Body Connection
Open Access
- Author:
- Fleeman, Rebecca
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 19, 2023
- Committee Members:
- Richard Mailman, Outside Field Member
Elizabeth Proctor, Co-Chair & Dissertation Advisor
Yongsoo Kim, Major Field Member
Amy Arnold, Outside Unit Member
Ralph Keil, Program Head/Chair
Kent Vrana, Co-Chair of Committee - Keywords:
- immunometabolism
alzheimer's disease
APOE4
cytokine signaling
multivariate modeling
neurodegeneration
aging
astrocytes
neurons - Abstract:
- Alzheimer’s disease (AD) is a neurodegenerative disease resulting in memory loss and cognitive impairment that affects over 50 million people globally. Currently, there is no curative treatment for AD and the molecular mechanisms of disease pathogenesis remain incompletely understood. The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for AD. While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. To determine the APOE4-driven concurrent effects of systemic metabolic changes and brain inflammation in young and aged mice, I used functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels to identify signatures of cytokines that are predictive of systemic metabolic outcomes, independent of AD proteinopathies. These findings led me to study cell-type-specific effects in the brain, to better understand how APOE4 leads to pathological signatures. Since APOE is a lipid transporter produced predominantly by astrocytes in the brain, and astrocytes provide various forms of support to neurons, I determined whether APOE4 alters astrocyte neuronal support functions. By measuring glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures, I discovered that treatment with APOE4 astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not due to differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Further, I found that astrocytic cytokine signatures could predict basal metabolism of neurons treated with the astrocytic conditioned media. Given the astrocytic effects observed with APOE4 and Aβ, I next turned to how APOE4 affects tau pathology in astrocytes. Studies of tau pathology in AD are classically neuron-centric and have overlooked cell-type-specific effects of tau internalization, degradation, and propagation. Herein, I showcase evidence for the importance of tau uptake by astrocytes and discuss the potential benefits and detriments to neuronal health based on the alteration of astrocytic immunometabolic reactions to tau. I present the first studies to identify a quantitative and predictive link between systemic metabolism and cytokine signaling in the brain, define specific pathological cytokine signatures in the brain of APOE mice across the lifespan, and determine that APOE3 and APOE4 astrocytic cytokine signatures predict basal metabolism of neurons treated with astrocytic factors. Together with my examination of the astrocytic uptake of pathological tau, I further suggest that astrocytic internalization of both Aβ and tau carries immunometabolic repercussions meriting further study. These findings highlight the AD-promoting effects of APOE4 in and beyond the brain, suggesting a bi-directional influence of AD risk factors in the brain and periphery driven by dysregulation of immunometabolism.