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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39247872/
Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease - PubMed Skip to main page content
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. 2024 Sep 5;8(1):1211-1228.
doi: 10.3233/ADR-240026. eCollection 2024.

Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease

Yiwen Yang  1 , Ming Tong  2 , Suzanne M de la Monte  2   3   4
Affiliations

Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease

Yiwen Yang et al. J Alzheimers Dis Rep. .

Abstract

Background: Alzheimer's disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk.

Objective: Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration.

Methods: Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs).

Results: Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ.

Conclusions: Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration.

Keywords: Alzheimer’s disease; alcohol; amyloid; cytokines; metabolism; neurodegeneration; neuroendocrine; rat model; tau.

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Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Moderate alcohol exposure effects on body weight, brain weight, blood alcohol concentration by sex. Long Evans male and female rats were maintained on isocaloric liquid diets containing 0% (control) or 24% ethanol (n = 8/group) for two weeks. A) Terminal mean body weights differed significantly by sex but not ethanol feeding. B) The mean brain weights did not differ significantly among the groups. C) Blood alcohol concentrations were significantly elevated by chronic ethanol feeding in both male and female rats. Results were analyzed by two-way mixed model ANOVA (Table 2) with post hoc Tukey tests. Significant inter-group differences are shown within the panels.
Fig. 2
Fig. 2
Large acidic ribonuclear protein (RPLPO) immunoreactivity. RPLPO immunoreactivity was used as a normalizing control. A) Immunoreactivity measured by direct binding ELISA is linearly correlated with protein content between 5 ng and 80 ng (r2 = 0.99). B) Boxplots of RPLPO immunoreactivity measured in 50 ng protein homogenate samples from frontal lobe control and ethanol-fed rats (n = 8/group). Inter-group comparisons were made by T-test. RPLPO immunoreactivity was used to normalize results obtained by duplex ELISAs in Fig. 3.
Fig. 3
Fig. 3
Effects of chronic moderate-level ethanol exposures on Long Evans rat frontal lobe levels of (A) AβPP, (B) Aβ, (C) Tau, (D) pTau, (E) ChAT, (F) AChE, (G) ASPH, and (H) GAPDH immunoreactivities (n = 8/group). Rats were maintained on isocaloric liquid diets containing 24% or 0% caloric ethanol for 2 weeks. Immunoreactivity was measured by duplex ELISA with results normalized to RPLPO. Results are depicted with boxplots that include individual (dots) and mean (horizontal bar) sample values, 95% confidence interval limits (top and bottom box limits), and ranges (stems). Inter-group statistical comparisons were made by two-way ANOVA (Table 3) and post hoc Tukey tests. Significant p-values are displayed within the panels. See Supplementary Figure 1 for heatmap corresponding to the within-group and between-group differences in the levels of immunoreactivity.
Fig. 4
Fig. 4
Ethanol exposure effects on frontal lobe expression of (A) ghrelin, (B) GLP-1, (C) glucagon, (D) leptin, and (E) PAI-1. Immunoreactivity was measured with a 5-Plex Diabetes Panel with equivalent amounts of protein per sample. Results are depicted with boxplots. Inter-group statistical comparisons (n = 8/group) were made by two-way ANOVA (Table 3) and post hoc Tukey tests. Significant p-values are displayed within the panels. (F) Heatmap displaying within-group and between-group differences in neuroendocrine polypeptide expression. The scale bar reflects pg/200 μg Protein.
Fig. 5
Fig. 5
Ethanol exposure effects on frontal lobe expression of (A) IL-1β, (B) IL-2, (C) IL-6, (D) IFN-γ, and (E) TNF-α in Long Evans rats (n = 8/group). Immunoreactivity was measured with a 5-Plex pro-inflammatory cytokine and chemokine panel with equivalent amounts of protein per sample. Results are depicted with boxplots that include individual mean sample values (dots). Inter-group statistical comparisons (n = 8/group) were made by two-way ANOVA (Table 3) and post hoc Tukey tests. Significant p-values are displayed within the panels. (F) Heatmap displaying within-group and between-group differences in cytokine/chemokine expression. The scale bar reflects the Log10-transformed pg/150 μg protein results.
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