Dissertation
Uncorking the truth: alcohol, serotonin, and the early stages of Alzheimer’s Disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007585
Abstract
There are no effective treatments for Alzheimer’s disease (AD) and related dementias, and existing interventions require early implementation, before significant pathological accumulation occurs. Because AD pathology often precedes symptoms by several decades, early identification for treatment is challenging. Modifiable risk factors, including lifestyle adjustments, thus represent promising targets for disease prevention. Recent epidemiological studies have highlighted alcohol use as one such risk factor, particularly in early-onset dementia. Though the association between alcohol consumption and AD remains underexplored, both alcohol use and AD pathology have notable impacts on the serotonin system, which may underlie this risk. This dissertation investigates how alcohol exposure may influence AD-like pathology and neuropsychiatric symptoms (NPS), focusing on serotonergic dysfunction as a potential mediator. Understanding how alcohol might accelerate the pathophysiology of dementia could help to identify at-risk individuals for early interventions.
We hypothesize that alcohol-induced serotonergic dysfunction may drive vulnerability to AD-related neuropathology and NPS, such as depression. To test this, we first utilized post-mortem human tissue and a preclinical mouse model to examine the role of tau pathology within the serotonergic system in relation to NPS-like behavior and serotonin neuron function. Tau pathology was found in the dorsal raphe nucleus (DRN) in 9 of 19 human cases without reported cognitive impairment, and in 9 of 10 AD cases. While this pathology was not exclusive to serotonergic neurons, it did colocalize with them. In wildtype mice overexpressing P301L-tau in the DRN, tau spread to connected regions, and was accompanied by depressive-like behaviors and hyperexcitability in serotonergic cells, possibly driven by tau-induced astrocytic activation.
Next, we assessed the effects of chronic alcohol exposure in a preclinical mouse model of spontaneous tau pathology (htau) and in wildtype mice. Chronic alcohol vapor induced a depressive-like phenotype in both htau and wildtype groups. Additionally, blood alcohol concentration correlated with tau pathology, serotonergic staining intensity, and tau-serotonin colocalization specifically in htau mice exposed to alcohol. Differential gene expression changes post-alcohol exposure in htau and wildtype mice suggest that alcohol may uniquely impact AD-related gene expression. These findings indicate a potential dose-dependent relationship between alcohol exposure and AD-like pathology, with serotonergic alterations mediating this risk. This work expands our understanding for the role of serotonin dysfunction in linking alcohol use to dementia risk, and provides insights that could aid in identifying at-risk individuals for whom lifestyle adjustments or early therapeutic interventions may be beneficial.
Details
- Title: Subtitle
- Uncorking the truth: alcohol, serotonin, and the early stages of Alzheimer’s Disease
- Creators
- Samantha Pierson
- Contributors
- Catherine Marcinkiewcz (Advisor)Marco Hefti (Committee Member)Ryan LaLumiere (Committee Member)Rainbo Hultman (Committee Member)Gordon Buchanan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007585
- Publisher
- University of Iowa
- Number of pages
- xvi, 229 pages
- Copyright
- Copyright 2024 Samantha Pierson
- Language
- English
- Date submitted
- 11/22/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 177-222).
- Public Abstract (ETD)
- Alzheimer’s disease (AD) has no cure, and existing treatments are only effective if applied very early—often decades before symptoms appear. My research seeks to illuminate how a common lifestyle choice—alcohol consumption—might shape this disease’s course by targeting serotonin and accelerating brain changes. Serotonin is a key neurotransmitter involved in mood regulation and memory. Though the association between alcohol consumption and AD remains underexplored, both alcohol use and AD pathology have notable impacts on the serotonin system, which may underlie this risk. My research has looked at the role alcohol exposure may play in AD-related brain changes, focusing on the buildup of tau—a protein that accumulates in AD—and its impact on the serotonin system. I found pathological tau protein in the serotonin-producing dorsal raphe nucleus (DRN) in individuals without AD using post-mortem samples. Next, I found that a preclinical mouse model with tau buildup in the DRN showed signs of depression-like behavior and changes in serotonin cell activity, suggesting a link between DRN tau pathology and AD-like symptoms. Having established a link between the DRN and AD symptoms, I then exposed a different tau mouse model to chronic alcohol. Results showed a relationship between blood alcohol levels and increases in both tau- and serotonin-related changes in the DRN. This suggests that alcohol could speed up brain changes associated with AD in a dose-dependent way. By understanding alcohol’s impact on AD risk, this research has implications for early intervention strategies through lifestyle adjustments and potential new treatments.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984774665602771
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