Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.
paper
Cited
Public
- Authors
- Hoffman, Jessica L; Faccidomo, Sara; Kim, Michelle; Taylor, Seth M; Agoglia, Abigail E; May, Ashley M; Smith, Evan N; Wong, L C; Hodge, Clyde W
- Year
- 2019
- Journal
- International review of neurobiology
- PMID
- 31733664
- DOI
- 10.1016/bs.irn.2019.10.017
- PMCID
- PMC6939615
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
Bioinformatic analysis of alcohol-sensitive protein networks in PFC and amygdala identified major mechanisms of AD (MAPT, APP, and PSEN1) as the statistically most likely upstream regulators. (A) Illustration of mouse home-cage drinking method and sample brain regions showing anatomical location of tissue punches. (B) Representative 2D-DIGE gels from each experiment. (C) Results of IPA Upstream Regulator Analysis that identified Alzheimer’s disease mechanisms as top regulators of alcohol-sensitive protein networks. (D) Alcohol-sensitive proteins detected in each brain region that are known to be downstream of MAPT, APP, and PSEN1. P values indicate significant overlap between AD regulator protein and alcohol-sensitive Alzheimer’s-linked molecules. Arrows indicate increase () or decrease () in expression after alcohol drinking. Data are shown as fold change representing the mean of four replicate gels. Proteins were included only if significantly changed in all four gels.
(A) Alzheimer’s disease progression showing mouse brain regional involvement and clinical symptoms as a function severity. (B) Graphic representation of the overall hypothesis of the present study: alcohol use (red line) exacerbates the onset (leftward time-dependent shift in age of onset) and magnitude (upward shift in degree) of AD-like pathology (black line).
Experimental timeline. Mice drank solutions (alcohol or saccharin) starting at 3 months of age for 4 months. Behavioral testing occurred after experimental solutions were removed. Behavioral testing occurred in the following sequence with a minimum of 1 day in between each test: Open field locomotion, rotarod, Morris Water Maze, prepulse inhibition, fear conditioning. Brains were collected at 8 months of age, 10 days after the final behavioral test.
No differences in alcohol or saccharin intake or motor function in 3xTg-AD mice as compared to WT controls. (A) Average alcohol intake (g/kg) and preference (% total fluid) from the 4-month access period plotted as a function of genotype. (B) Average saccharin intake (mL) and preference (% total fluid) plotted as a function of genotype. (C) Average body weight (g) of WT and 3xTg-AD mice at 10 weeks of age (male and female combined). (D) Spontaneous locomotor behavior and habituation to an unfamiliar environment. Mice were placed in locomotor activity chambers, and distance traveled was measured during a single session. (E) Rotarod performance by 3xTg-AD and WT mice expressed as average latency to fall (s) over three trials. Data are shown as mean SEM. No statistically significant differences were detected between genotypes or alcohol/saccharin condition.
Alcohol drinking-induced behavioral deficits in 3xTg-AD mice. (A, left) Average escape latency (s) plotted as a function of trial during Morris Water Maze acquisition. * indicates significant main effect between genotypes over all trials. (A, right) Percentage of time (s) spent in the quadrant of the Morris Water Maze that previously contained the escape platform. * indicates significant difference between alcohol vs saccharin exposed 3xTg-AD mice, P < 0.05. (B) Average prepulse inhibition (%) plotted as a function of stimulus intensity (dB). * indicates statistically significant main effect between 3xTg-AD mice that consumed alcohol vs saccharin. (C, left) Cued fear response plotted as average freezing (% control seconds) as a function of genotype and alcohol intake condition. * indicates significant difference between 3xTg-AD mice that consumed alcohol vs saccharin, P < 0.05. (C, right) Context-dependent fear response plotted as freezing (% control) as a function of genotype and treatment conditions. Abbreviations: Saccharin (Sacc), Alcohol (Alc).
AD biomarker protein expression in specific brain regions of 3xTg-AD mice at 1-month post alcohol drinking. The title above each graph shows brain region and the AT(N) rubric for biomarker interpretation (see Table 2). (A-D, left) Mean ± SEM Aβ (42/40) ratio. (A-D, right) Total Tau protein expressed as mean ± SEM background corrected Median Fluorescence Intensity (MFI). Measures are plotted as a function of drinking history (S—saccharin; A—alcohol). * P < 0.05; ** P < 0.01, A vs S, t-test. WT control wells exhibited expression at background levels (data not shown).
pTau-Ser199/202 immunoreactivity (IR) in WT and 3xTg-AD mice 1-month post alcohol or saccharin drinking. (A) Coronal sections of dorsal hippocampus showing prominent IR in neuronal cell bodies and projections of CA1 only in 3xTg-AD mice with upregulation post alcohol (EtOH). (B) Basolateral amygdala (BLA) sections showing no alcohol-induced difference in pTau-Ser199/202 IR. Images acquired on Olympus BX51 microscope at 10× magnification.
| # | Section | Preview |
|---|---|---|
| 80 | Results and discussion — NIA-AA biomarker analysis in specific brain regions of 3xTg-AD mice (1-month post alcohol) — Medial prefrontal cortex (mPFC) and amygdala (AMY) | Alcohol had no effect on the Aβ (42/40) ratio in the mPFC or AMY. However alcohol drinking was… |
| 81 | Results and discussion — NIA-AA biomarker analysis in specific brain regions of 3xTg-AD mice (1-month post alcohol) — Additional brain regions | No changes in Aβ42/40 ratio or total Tau protein were detected in samples from nucleus accumbens… |
| 82 | Results and discussion — NIA-AA biomarker analysis in specific brain regions of 3xTg-AD mice (1-month post alcohol) — Biomarker conclusions | First, based on evidence that 6–8-month-old 3xTg-AD mice exhibit AD-like pathology expressed as… |
| 83 | Results and discussion — Tau pathology: Hyperphosphorylation of Tau at GSK3β site in 3xTg-AD mice (1-month post alcohol) | The presence of paired helical fragments formed by hyperphosphorylation of microtubule-associated… |
| 84 | Results and discussion — Tau pathology: Hyperphosphorylation of Tau at GSK3β site in 3xTg-AD mice (1-month post alcohol) | Although Tau is phosphorylated by numerous kinases, evidence indicates that glycogen synthase… |
| 85 | Results and discussion — Tau pathology: Hyperphosphorylation of Tau at GSK3β site in 3xTg-AD mice (1-month post alcohol) | 3xTg-AD and WT mice were sacrificed 1month after alcohol or saccharin drinking (as described above)… |
| 86 | Results and discussion — Tau pathology: Hyperphosphorylation of Tau at GSK3β site in 3xTg-AD mice (1-month post alcohol) | The results of this study are consistent with prior findings in 3xTg-AD mice showing age-dependent… |
| 87 | Results and discussion — Tau pathology: Hyperphosphorylation of Tau at GSK3β site in 3xTg-AD mice (1-month post alcohol) | present results show that alcohol-exposed 3xTg-AD mice have deficits in spatial memory (Fig. 5A) and… |
| 88 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) | To gain further understanding of the long-lasting impact of chronic nondependent alcohol drinking on… |
| 89 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) | alcohol treatment and withdrawal (Faccidomo et al., 2019; Neasta, Ben Hamida, Yowell, Carnicella, &… |
| 90 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) | In the present study, the brains of 3xTg-AD mice were probed for changes to phosphoproteins of the… |
| 91 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Hippocampus | In three subregions of the HPC, (medial, lateral, and CA1) analyzed in this study, the effects on… |
| 92 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Hippocampus | These results indicate that a history of alcohol drinking is associated with downregulation of… |
| 93 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Hippocampus | In the 3xTgAD mice, prior studies have found decreased levels of IRS-1 in the membrane fraction of… |
| 94 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Hippocampus | In previous studies of AD, P70S6K is more often reported to be increased (An et al., 2003; Jin-Jing,… |
| 95 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Entorhinal cortex | The entorhinal cortex is sensitive to early AD pathology and this is reflected in both the brain and… |
| 96 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Entorhinal cortex | = 1.905, P = 0.047], IR [t(8) = 2.211, P = 0.029], and PTEN [t(8) = 1.976, P = 0.042]; while in the… |
| 97 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Amygdala | In the AMY, a history of alcohol drinking was associated with a significant decrease in… |
| 98 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Amygdala | This finding is consistent with prior work showing that ERK1/2 phosphorylation is reduced in the AMY… |
| 99 | Results and discussion — Analysis of Akt/mTOR phosphoprotein pathway throughout the brain after chronic alcohol: Decreased expression of multiple mTOR/Akt phosphoproteins in 3xTg-AD alcohol-exposed mice (1-month post alcohol) — Conclusions | The mTOR/Akt pathway is critical in the regulation of cell growth, proliferation, and… |
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. | 2021 | 34417470 |
External
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| Acute and Chronic Ethanol Effects during Adolescence on Neuroimmune Responses: Consequences and Potential Pharmacologic Interventions. | Nwachukwu KN et al. | — | 2023 | → |
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| A perspective on autophagy and transcription factor EB in Alcohol-Associated Alzheimer's disease. | Zhang C et al. | — | 2023 | → |
| A subchronic history of binge-drinking elicits mild, age- and sex-selective, affective, and cognitive anomalies in C57BL/6J mice. | Jimenez Chavez CL et al. | — | 2023 | → |
| Chemical Genetic Identification of PKC Epsilon Substrates in Mouse Brain. | Dugan MP et al. | — | 2023 | → |
| Discrepancy of synaptic and microtubular protein phosphorylation in the hippocampus of APP/PS1 and MAPT×P301S transgenic mice at the early stage of Alzheimer's disease. | Wang Q et al. | — | 2023 | → |
| Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders. | Gupta R et al. | — | 2023 | → |
| Dysregulation of tryptophan metabolism and distortion of cell signaling after oral exposure to ethanol and Kynurenic acid. | Yang C et al. | — | 2023 | → |
| Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism in APP/PS1 mice. | Day SM et al. | — | 2023 | → |
| Fetal alcohol exposure impairs learning and memory functions and elevates levels of various biochemical markers of Alzheimer's disease in the brain of 12-month-old rats. | Chaudhary S et al. | — | 2023 | → |
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| Inflammation and aging: signaling pathways and intervention therapies. | Li X et al. | — | 2023 | → |
| Neuroprotective Effects of IVIG against Alzheimer' s Disease via Regulation of Antigen Processing and Presentation by MHC Class I Molecules in 3xTg-AD Mice. | Fei Z et al. | — | 2023 | → |
| Precocious emergence of cognitive and synaptic dysfunction in 3xTg-AD mice exposed prenatally to ethanol. | Tousley AR et al. | — | 2023 | → |
| Prenatal alcohol exposure causes persistent microglial activation and age- and sex- specific effects on cognition and metabolic outcomes in an Alzheimer's Disease mouse model. | Walter KR et al. | — | 2023 | → |
| Schedule-induced alcohol intake during adolescence sex dependently impairs hippocampal synaptic plasticity and spatial memory. | Sanz-Martos AB et al. | — | 2023 | → |
| Sex-specific effects of ethanol consumption in older Fischer 344 rats on microglial dynamics and Aβ<sub>(1-42)</sub> accumulation. | Marsland P et al. | — | 2023 | → |
| Substance abuse and neurodegenerative diseases: focus on ferroptosis. | Guo C et al. | — | 2023 | → |
| Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice. | Downs AM et al. | — | 2023 | → |
| The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration. | Masi M et al. | — | 2023 | → |
| Adolescent Binge Alcohol Enhances Early Alzheimer's Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation. | Barnett A et al. | — | 2022 | → |
| Alcohol-Drinking Under Limited-Access Procedures During Mature Adulthood Accelerates the Onset of Cognitive Impairment in Mice. | Jimenez Chavez CL et al. | — | 2022 | → |
| Chromatin architecture in addiction circuitry identifies risk genes and potential biological mechanisms underlying cigarette smoking and alcohol use traits. | Sey NYA et al. | — | 2022 | → |
| Chronic Ethanol Causes Persistent Increases in Alzheimer's Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment. | Tucker AE et al. | — | 2022 | → |
| Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder. | Tye SJ et al. | — | 2022 | → |
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| <i>DPYSL2</i>/<i>CRMP2</i>isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders | Feuer KL et al. | — | 2022 | — |
| Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease. | Frausto DM et al. | — | 2022 | → |
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| Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. | Kapoor M et al. | — | 2021 | → |
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