This review aims to determine the connection between developmental alcohol exposure and its potential impact on Alzheimer's disease (AD) later in life. We employ a network meta-analysis approach and examine gene fold changes from literature and Gene Expression Omnibus (GEO) datasets. Our goal is to investigate whether prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate specific neuroinflammatory genes, potentially increasing the risk of AD development.
We conducted a comprehensive analysis of brain datasets using a network meta-analysis approach. By synthesizing gene fold changes from literature and GEO datasets, we examined the potential impact of developmental alcohol exposure on increased risk of developing AD in the future.
Our findings reveal significant associations between alcohol exposure and critical functional categories and diseases in the brain. Alcohol exposure was strongly linked to the “Inflammatory Response” and “Nervous System Development and Function” categories, indicative of inflammatory reactions in the brain and detrimental effects on nervous system integrity. Furthermore, we observed links with “Organismal Injury and Abnormalities” and “Cell Death and Survival.” Pathway analysis revealed dysregulation in neuroinflammatory, ERK/MAPK signaling, amyloid processing, IL-1 signaling and calcium signaling pathways, suggesting their potential involvement in alcohol-induced neurotoxicity.
This review highlights the necessity of recognizing developmental alcohol exposure as a potential risk factor for AD and shed light on the underlying mechanisms that may contribute to alcohol-induced neurotoxicity. By expanding our understanding of these mechanisms, we can better address the complex relationship between developmental alcohol exposure and neurodegenerative disorders like AD.
Alcohol is a substance commonly used in American society. About fourteen million Americans reach the clinical criteria for alcohol use disorder, with nine percent of alcohol-dependent patients being diagnosed with brain disorders. Alcohol-related cognitive impairment is the second leading cause of adult dementia in the United States, being exceeded only by AD . While the association between alcohol and adult dementia is well studied , , , , there are few studies done about whether developmental exposure to alcohol promotes Alzheimer’s disease later in life. Fetal alcohol spectrum disorders (FASD) are caused by the exposure of the fetus to ethanol during pregnancy. Damage to the central nervous system is a common side effect of fetal alcohol exposure and is an important cause of developmental intellectual disability [5, 6]. Estimated rate of FASD is between 2.0 and 6.7 % and is the leading cause of mental retardation worldwide . The neuropathology of FASD includes a reduced volume of the cerebral cortex, corpus callosum, cerebellum, and structures of the subcortex including the amygdala, basal ganglia, hippocampus, and thalamus [8–13]. FASD also causes memory and learning disorders, and problems with the processing of information , , . Fetal alcohol exposure (FAE) has been demonstrated to induce specific biochemical and behavioral phenotypes that exhibit notable similarities to features observed in AD pathology . In a rat study by Chaudhary and Sarkar, FAE increased levels of AD-related markers such as acetylcholinesterase, hyperphosphorylated-tau protein, β-amyloid, BACE1, and UNC5C proteins in the cerebral cortex and hippocampus and AD-related behavioral phenotypes like impairment of learning and memory functions . These findings suggest that FAE could promote biochemical and cognitive traits akin to Alzheimer’s disease. In addition to FASD caused by ethanol exposure during gestation, alcohol use during the period of brain development in adolescence may also be harmful [8, 18, 19].
Adolescence is a stage of the developing brain during which changes in the structure and function of synaptic plasticity and the connections of neurons occur in various brain regions, such as the subcortical and cortical structures . Alcohol exposure during adolescence period may lead to long-term cognitive and behavioral dysfunctions [21, 22]. Exposure to alcohol in the developing central nervous system (CNS) can alter the functions of neurons directly [23, 24] or via modification of the functions of glial cells such as astrocytes and microglia which maintain the homeostatic environment [10, 25, 26]. While these glial cells operate as the immune system in the CNS and defend against pathogens and other insults, their activation can also damage the CNS and lead to aberrant CNS function , , . While the exact effects of ethanol in the developing brain are still not fully untangled, there is evidence that the response of the neuroimmune system is involved [26, 30, 31].
Current evidence from neuropathology and genetic studies suggests that AD may involve an amyloid cascade, which leads to the degeneration of neurons due to the accumulation of amyloid beta plaques in the brain [32–37]. Neurofibrillary tangles, which are intracellular aggregates of hyperphosphorylated tau protein, are another cause of AD , , . The role of neuroinflammation in AD is supported by evidence that microglia are activated by cellular death or neurofibrillary tangles and cause an immune response mediated by danger or pathogen-associated molecular pattern receptors called DAMPS/PAMPS [41–50]. Mouse models have demonstrated that the selective elimination of microglia, achieved through pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R) signaling, is associated with a reduction in neuronal loss and amelioration of memory impairments in AD . The most relevant type of cellular death in AD is apoptosis, which is a type of regulated cell death. The intrinsic pathway of apoptosis, controlled by the pro-apoptotic proteins BAX and BAD from the family Bcl-2, is upregulated in the frontal cortex and hippocampus of AD mouse models [52, 53]. In this study, loss of Bad prevented neuronal apoptosis and degeneration and restored behavioral alterations and cognitive decline. These findings suggest that neuroinflammation and apoptosis are key processes in the pathogenesis of AD and may be important targets for therapeutic intervention. Finally, excessive glutamate released from damaged neuronal cells and microglia in AD leads to calcium influx through N-methyl-d-aspartate receptors (NMDARs), which can cause cellular damage , , , . NMDARs are protein complexes with GluN1 and GluN2 subunits that modulate intracellular signaling pathways via Ca2+ influx through an ionic pore . Overactivation of NMDARs leads to neuronal cell death through apoptosis involving excess calcium release, depolarization of mitochondria, and activation of cytochrome c and caspase-3 [56, 57]. Dysregulated amyloid precursor protein (APP) processing by microglia and excessive NMDA receptor (NMDAR) activation due to glutamate release from degenerating neurons have been implicated in the formation of neurofibrillary tangles, contributing to increased neuronal cell death .
Extensive research has focused on elucidating the role of neuroinflammation in AD development. Additionally, investigations have explored the influence of developmental alcohol exposure on the neuroinflammatory processes associated with AD. However, the specific effects of early-life alcohol exposure on the development of AD have yet to be determined. In this study, we used a meta-analysis approach to determine if prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate key neuroinflammatory genes for an increased risk of developing AD later in life.
Ingenuity Pathway Analysis software
In this study, we performed a network meta-analysis using QIAGEN Ingenuity Pathway Analysis (IPA) to identify the effects of PAE and AAE on differentially expressed genes and their relationship to neuroinflammation and Alzheimer’s disease. The IPA Analysis Match CL license was purchased from QIAGEN (QIAGEN, Germantown, MD; QIAGEN Inc., https://www.QIAGENbioinformatics.com/products). IPA is a bioinformatics program that operates using computerized algorithms to determine the operant connections of genes using QIAGEN Knowledge Base (QKB), a comprehensive database of over seven million different relationships between drugs, diseases, genes, proteins metabolites, and other biological processes . While traditional meta-analysis such as that described by Tabakoff et al.  uses regular statistical analysis tools to identify differentially expressed genes , the Qiagen IPA software uses highly developed bioinformatics methods such as Benjamini–Hochberg’s Corrected Fisher’s Exact Test to identify differentially expressed genes and the significance of their association with different canonical, disease and functional, and upstream regulator pathways. As described by Krämer et al. , IPA analysis uses a suite of algorithms to generate either a positive or negative z-score for each molecule or canonical pathway that determines its statistical significance and whether it is associated with the activation or inhibition of individual molecules and/or pathways . We used the bioinformatics tools available in IPA to analyze the statistical significance of differentially expressed genes and their association with canonical, disease, functional, and upstream regulator pathways.
Identification of molecules impacted by neuroinflammation and Alzheimer’s disease
Using IPA’s “Build”-“Grow” tool molecules, including genes, proteins, and complexes that exist in organisms in nature, affected by neuroinflammation and/or AD were obtained from QKB.
Collection of molecules affected by prenatal/adolescent alcohol exposure
Molecules affected by PAE [including fetal alcohol exposure (FAE), gestational alcohol exposure (GAE), neonatal alcohol exposure (NAE), fetal alcohol spectrum disorder (FASD)], and AAE were gathered from a literature search of MEDLINE via Pubmed (PubMed.gov) before October 20, 2022, which showed a total of 22,936 articles, including possible duplicates, for PAE and 6745 for AAE usage (Figure 1). Within these results, 2047 papers covered the effects of PAE and/or AAE exposure on neurotoxic or neuroinflammatory pathways, with 163 articles showing the effects of such pathways on gene expression. Out of these 163 articles describing gene expression of alcohol’s effects on developmental neuroinflammatory pathways, we selected 32 articles that best identified the differential expression of genes upon exposure to PAE/AAE in mouse, rat, and human subjects (Figure 2a). We also identified 38 datasets from the Gene Expression Omnibus database located at the NCBI website which demonstrated the effects of PAE or AAE on gene expression in the brains of mice, rats, and humans (Figure 2c). According to the IPA website, IPA software cannot interpret raw microarray data and this function can only be performed with a separate tool called CLC workbench. Out of these 38 RNA-seq datasets from mouse, rat, and human GEO entries, only nine were not based on microarrays or had array genetic data published in a publicly available study and demonstrated statistically significant effects of PAE and/or AAE on neuroinflammatory pathways above the threshold cutoff value.
Due to the subject of this paper being PAE and AAE, only control and alcohol-exposed groups were selected from our GEO dataset search. If any duplicate categories of control or ethanol-exposed groups were found in a dataset, we calculated the average value for each group. Next, the gene expression fold change was calculated by dividing the gene expression values for ethanol-exposed groups by the value of the control group. The log2 of the fold change for each gene was then determined and an Excel spreadsheet was then placed into IPA for analysis (Figure 2c). The aforementioned steps were performed for each mouse, rat, and human dataset. Genes showing significant differences between PAE and AAE were selected to construct a pathway analysis map in IPA. Homologs were not converted between species. Data sets were analyzed under identical parameters and the cut-off was set from −1 to +1. Genes with reported significant expression level changes between the control values and PAE and/or AAE in the literature were identified as molecules affected by EtOH (p<0.05) and added to a pathway in IPA using its “Build, Add molecules/relationship” tool. Data sets were studied using IPA software to identify the neuroinflammatory genetic network. The analysis of GEO datasets was performed using the Canonical Pathway tool. In gene expression studies where thousands of genes are measured between two experimental conditions, the false discovery rate (FDR) is a concern. The False Discovery Rate (FDR) represents the risk of encountering false positive results when conducting multiple tests. In this study, we used IPA to employ a technique devised by Benjamini and Hochberg to identify and remove such false positives caused by FDR . Each IPA analysis generated either a positive or negative z score for all canonical and individual molecules involved in each pathway which indicated its activation or inhibition respectively. The set of molecules that were found to be affected by literature and GEO datasets were then added to a pathway window in IPA. Connections between these molecules were then identified using the “Connect” tool using the focused results of QKB.
IPA for core analysis
In our analysis, we used IPA to identify the Canonical Pathways associated with PAE/AAE exposure in mice, rat, and human GEO datasets. Canonical pathway analysis was used to identify pathways affected by PAE/AAE based on the connections of molecules affected by PAE/AAE to the 705 canonical pathways stored in QKB. The significance of the association with each of these 705 canonical pathways was calculated using a Benjamini–Hochberg corrected Fisher’s exact test. The p-value demonstrated the odds of discovering the number of overlapping molecules from a dataset in a canonical pathway.
IPA analysis of alcohol-exposed brain datasets using the Disease and Functional Analysis tool revealed significant associations between alcohol exposure and various functional categories and diseases. Notably, multiple datasets showed a strong association between alcohol exposure and the “Inflammatory Response” category (GSE184615, p=1.0e-07; GSE14714, p=1.0e-12; GSE154018, p=6.9e-03; GSE63561, p=5.0e-03; GSE133369, p=5.0e-03; GSE195489, p=1.0e-04; GSE60901, p=1.0e-04; GSE34469, p=1.0e-05; GSE115188, p=1.0e-05), indicating that alcohol exposure elicits an inflammatory response in the brain.
Additionally, alcohol exposure was significantly associated with “Nervous System Development and Function” in multiple datasets (GSE154018, p=1.0e-05; GSE184615, p=1.0e-14; GSE14714, p=1.0e-17; GSE195489, p=4.0e-03; GSE60901, p=3.0e-03; GSE34469, p=1.0e-05; GSE115188, p=1.0e-06), suggesting detrimental effects on the development and functioning of the nervous system.
Furthermore, alcohol exposure exhibited significant associations with the “Organismal Injury and Abnormalities” category (GSE184615, p=1.0e-08; GSE14714, p=1.0e-23; GSE133369, p=1.0e-05; GSE63561, p=1.0e-05; GSE195489, p=1.0e-14; GSE60901, p=1.0e-14; GSE34469, p=1.0e-04; GSE115188, p=1.0e-05), indicating potential adverse effects on overall organismal health.
The category “Cell Death and Survival” also showed significant associations with alcohol exposure (GSE133369, p=1.0e-05; GSE63561, p=5.0e-05; GSE154018, p=1.0e-04; GSE184615, p=1.0e-04; GSE195489, p=1.0e-04; GSE60901, p=1.0e-04; GSE34469, p=1.0e-07; GSE115188, p=1.0e-04), suggesting increased cell death in the brain due to alcohol exposure.
Moreover, the “Neurological Disease” category displayed significant associations with alcohol exposure (GSE115188, p=3.595e-04; GSE154018, p=1.0e-06; GSE184615, p=1.0e-05; GSE14714, p=1.0e-23; GSE133369, p=1.0e-04; GSE63561, p=1.0e-05; GSE195489, p=1.0e-06; GSE60901, p=1.0e-06; GSE34469, p=1.0e-04).
Furthermore, canonical pathway analysis revealed additional significant associations between alcohol exposure and specific pathways. The “Neuroinflammation Signaling Pathway” showed significant associations with alcohol exposure in multiple datasets (GSE14714, p=0.16; GSE34469, p=0.018; GSE60901, p=0.203; GSE63651, p=0.463). The “ERK/MAPK Signaling” pathway was significantly associated with alcohol exposure in several datasets (GSE14714, p=0.021; GSE60901, p=0.151; GSE63651, p=0.422; GSE115188, p=0.422). Additionally, the “Amyloid Processing” pathway showed significant associations with alcohol exposure in multiple datasets (GSE14714, p=0.012; GSE60901, p=0.176; GSE63651, p=0.512; GSE115188, p=0.341). The “IL-1 Signaling” pathway was significantly associated with alcohol exposure in several datasets (GSE14714, p=0.008; GSE34469, p=0.445; GSE60901, p=0.342; GSE115188, p=0.342). Finally, the “Calcium Signaling” pathway showed significant associations with alcohol exposure in multiple datasets (GSE14714, p=0.002; GSE34469, p=0.008; GSE60901, p=0.295; GSE63651, p=0.464; GSE115188, p=0.464).
In addition to these findings, the “Oxidative Phosphorylation” pathway was significantly associated with alcohol exposure in several datasets (GSE34469, p=0.016; GSE60901, p=0.322; GSE63651, p=0.422; GSE115188, p=0.422). These results suggest that alcohol exposure may impact oxidative phosphorylation processes in the brain.
In order to further explore the potential interactions and pathways involved in the neuroinflammatory processes associated with prenatal and adolescent alcohol exposure (PAE/AAE) and Alzheimer’s disease (AD), we conducted a network analysis using the Build/Grow and Connect tools. First, we identified molecules that were common to both the gene expression omnibus (GEO) datasets and the literature. These molecules were cross referenced with genes associated with neuroinflammation and AD obtained from the Qiagen Knowledge Base.
Figure 5 illustrates the results of this network analysis, highlighting the potential involvement of several cytokines and signaling molecules. These include TGF-β, TNF-β, IFN-β, CXCL8, IL1-β, B2M, BCL2, BDNF, CALB2, CASP1, CASP3, CASP8, CD86, CNTF, CX3CL1, CCL2, FOS, MYD88, GABRA1, GABRA2, GABRA4, GABRA5, GABRB3, NFKB, GABRD, GABRG1, GABRG2, GABRQ, GABRR1, BARR2, GRIN2A, GRIN2D, HMOX1, IL10, IL4, IL6, MAPK1, MAPK3, NOS2, TLR4, and TRAF6. These molecules may play a role in the PAE/AAE-associated neuroinflammatory signaling pathways and/or AD.
Our study focused on investigating the effects of alcohol exposure on the brain, with a particular emphasis on neuroinflammation and its potential association with the development of neurological disorders, including AD. Through our analysis of disease and functional categories in alcohol-exposed brain datasets, we observed significant associations with neuroinflammation, nervous system development and function, organismal injury and abnormalities, cell death and survival, as well as neurological disease (Figure 3). These findings underscore the detrimental impact of alcohol exposure on the brain, disrupting normal brain functioning and potentially contributing to the development of neurological disorders (Figure 4).
Furthermore, our study utilized canonical pathway analysis to provide additional support for the involvement of alcohol exposure in neuroinflammatory processes and the dysregulation of critical signaling pathways. The Neuroinflammation Signaling pathway exhibited a significant association with alcohol exposure, suggesting that alcohol may induce neuroinflammatory responses in the brain. Dysregulated ERK/MAPK signaling, crucial for synaptic plasticity and cell survival, implies that alcohol exposure during critical stages of brain development may disrupt normal signaling processes, potentially leading to neurofunctional impairments .
We also observed the dysregulation of the Amyloid Processing pathway, which is implicated in the pathogenesis of Alzheimer’s disease , , , , . This finding suggests a potential link between alcohol exposure, neuroinflammation, and the development of neurodegenerative disorders. The significant association between alcohol exposure and the IL-1 Signaling pathway, involved in inflammatory responses, further supports the involvement of inflammatory processes in alcohol-induced neurotoxicity. Additionally, the dysregulation of the Calcium Signaling pathway, critical for neuronal function and synaptic plasticity , highlights the potential impact of alcohol exposure on neurotoxicity and neurodevelopment.
Taking these findings together, our study provides valuable insights into the molecular and functional consequences of alcohol exposure on the brain. The identification of associations with neuroinflammation, dysregulated signaling pathways, and the involvement of critical pathways related to neurodegenerative disorders enhances our understanding of the mechanisms underlying the neurotoxic effects of alcohol. This knowledge is essential for comprehending the pathogenesis of neurological disorders, particularly Alzheimer’s disease, and may inform preventive strategies and interventions.
In the context of our study, Figure 5 depicts the results concerning the potential involvement of various cytokines and signaling molecules in the neuroinflammatory signaling pathways and/or Alzheimer’s disease associated with prenatal and adolescent alcohol exposure (PAE/AAE). Notably, several cytokines, including TGF-β, TNF-β, IFN-β, CXCL8, and IL1-β, were found to be associated with both neuroinflammation and AD. Prior research has implicated these cytokines in neuroinflammatory processes and demonstrated their upregulation in the brains of individuals with AD [63, 64]. The dysregulation of these cytokines in the context of PAE/AAE suggests their potential involvement in the neuroinflammatory response triggered by alcohol exposure, thereby potentially contributing to the development or progression of AD.
Furthermore, our study identified various signaling molecules, such as B2M, BCL2, BDNF, CALB2, CASP1, CASP3, CASP8, CD86, CNTF, CX3CL1, CCL2, FOS, MYD88, GABRA1, GABRA2, GABRA4, GABRA5, GABRB3, NFKB, GABRD, GABRG1, GABRG2, GABRQ, GABRR1, BARR2, GRIN2A, GRIN2D, HMOX1, IL10, IL4, IL6, MAPK1, MAPK3, NOS2, TLR4, and TRAF6, within the context of PAE/AAE, neuroinflammation, and AD. These molecules play diverse roles in various cellular processes, including apoptosis, neuroplasticity, immune responses, and synaptic functions [63–71]. PAE/AAE effects during developmental period may permanently change the normal brain development and functions and make the exposed brain vulnerable for the development of AD.
We found PAE/AAE altered expression levels of the neurotrophic factors BDNF and CNTF. Throughout the prenatal and adolescent phases, neurotrophic factors BDNF and CNTF play pivotal roles in nurturing neuronal vitality and fostering synaptic plasticity [66, 67]. BDNF and CNTF, critical during brain development, may influence AD vulnerability through their effects on early synaptic plasticity . We also found changes in the GABA receptor subunits (GABRA1, GABRA2, GABRA4, GABRA5, GABRB3, GABRD, GABRG1, GABRG2, GABRQ, GABRR1) and the NMDA receptor subunit GRIN2A. Proper GABAergic function during developmental stages is crucial for establishing a balanced neural network, and disturbances could promote the AD-related neuronal imbalances [69, 70]. We detected changes in the apoptotic signaling molecules BCL2, CASP1, CASP3, and CASP8 due to PAE/AAE exposures. During the prenatal period, disturbances in BCL2, CASP3, and CASP8-mediated survival mechanisms could play pivotal roles in shaping the susceptibility to neuronal loss observed in AD , , . PAE/AAE exposures also affected CD86, CCL2, TLR4, and MYD88 known to be involved in proinflammatory immune response [74, 75]. PAE/AAE could potentially prime the immune system towards a pro-inflammatory state, thereby contributing to the neuroinflammatory milieu inherent in AD . Molecules like NFKB, FOS, and MAPKs (MAPK1 and MAPK3) are also affected by PAE/AAE. Disruptions in these molecules may compromise stress responses, synaptic plasticity, and cognitive function [77, 78], which is often observed in AD. Furthermore, HMOX1, IL10, IL4, and IL6, known to be involved in regulating oxidative stress and/or inflammation [79, 80], are also identified. PAE/AAE-induced alterations in these molecules might accentuate oxidative damage and spur neuroinflammatory cascades, thereby potentially heightening AD susceptibility. We identified PAE/AAE altered expression of CALB2 and CX3CL1 that are involved in calcium signaling and neuroprotection [81, 82]. Their roles could impact neuronal health and AD susceptibility through their effects on calcium homeostasis and neuroprotective mechanisms.
In summary, our study underscores the potential involvement of a wide range of cytokines and signaling molecules in PAE/AAE-associated neuroinflammatory signaling pathways and/or Alzheimer’s disease. These findings contribute to our understanding of the molecular mechanisms underlying the neurotoxic effects of alcohol exposure and their potential contribution to the development of neurological disorders, including AD. Further research focused on elucidating the specific roles of these molecules and their interactions within neuroinflammatory pathways is critical for a comprehensive understanding of AD’s pathogenesis and the development of targeted interventions to mitigate the detrimental effects of alcohol on the brain. Raising awareness about the adverse effects of alcohol exposure, particularly during critical periods of brain development, and promoting preventive measures are imperative for reducing the risk of neuroinflammation and associated neurological diseases.
Funding source: National Institute of Health
Award Identifier / Grant number: T32AA028254 and R01AA025359
Informed consent: Not applicable.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Research funding: This work was supported by National Institute of Health grants T32AA028254 and R01AA025359.
Ethical approval: Not applicable.
1. U.S. Department of Health and Human Services. 10th annual report to congress on alcohol and health from the secretary of health and human Services public health service. Rockville, MD: National Institutes of Health. National Institute on Alcohol Abuse and Alcoholism; 2000.Search in Google Scholar
2. Mewton, L, Visontay, R, Hoy, N, Lipnicki, DM, Sunderland, M, Lipton, RB, et al.. Collaborators from the Cohort Studies of Memory in an International Consortium (COSMIC). The relationship between alcohol use and dementia in adults aged more than 60 years: a combined analysis of prospective, individual-participant data from 15 international studies. Addiction 2023;118:412–24. https://doi.org/10.1111/add.16035.Search in Google Scholar PubMed PubMed Central
3. Venkataraman, A, Kalk, N, Sewell, G, Ritchie, CW, Lingford-Hughes, A. Alcohol and Alzheimer’s disease-does alcohol dependence contribute to beta-amyloid deposition, neuroinflammation and neurodegeneration in Alzheimer’s disease? Alcohol Alcohol 2017;52:151–8. https://doi.org/10.1093/alcalc/agw092.Search in Google Scholar PubMed
4. Piazza-Gardner, AK, Gaffud, TJ, Barry, AE. The impact of alcohol on Alzheimer’s disease: a systematic review. Aging Ment Health 2013;17:133–46. https://doi.org/10.1080/13607863.2012.742488.Search in Google Scholar PubMed
5. Mela, M, Coons-Harding, KD, Anderson, T. Recent advances in fetal alcohol spectrum disorder for mental health professionals. Curr Opin Psychiatry 2019;32:328–35. https://doi.org/10.1097/yco.0000000000000514.Search in Google Scholar PubMed
7. May, PA, Hasken, JM, Hooper, SR, Hedrick, DM, Jackson-Newsom, J, Mullis, CE, et al.. Estimating the community prevalence, child traits, and maternal risk factors of fetal alcohol spectrum disorders (FASD) from a random sample of school children. Drug Alcohol Depend 2021;227:108918. https://doi.org/10.1016/j.drugalcdep.2021.108918.Search in Google Scholar PubMed PubMed Central
8. Crews, FT, Sarkar, DK, Qin, L, Zou, J, Boyadjieva, N, Vetreno, RP. Neuroimmune function and the consequences of alcohol exposure. Alcohol Res 2015;37:344–51.Search in Google Scholar
9. Drew, PD, Johnson, JW, Douglas, JC, Phelan, KD, Kane, CJ. Pioglitazone blocks ethanol induction of microglial activation and immune responses in the hippocampus, cerebellum, and cerebral cortex in a mouse model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 2015;39:445–54. https://doi.org/10.1111/acer.12639.Search in Google Scholar PubMed PubMed Central
10. Chastain, LG, Sarkar, DK. Role of microglia in regulation of ethanol neurotoxic action. Int Rev Neurobiol 2014;118:81–103. https://doi.org/10.1016/B978-0-12-801284-0.00004-X.Search in Google Scholar PubMed
11. Kane, CJ, Phelan, KD, Han, L, Smith, RR, Xie, J, Douglas, JC, et al.. Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders. Amsterdam, Netherlands: Elsevier; 2011.10.1016/j.bbi.2011.02.016Search in Google Scholar PubMed PubMed Central
12. Tiwari, V, Chopra, K. Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain. J Neurochem 2011;117:678–90. https://doi.org/10.1111/j.1471-4159.2011.07236.x.Search in Google Scholar PubMed
13. Fernandez-Lizarbe, S, Pascual, M, Guerri, C. Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol 2009;183:4733–44. https://doi.org/10.4049/jimmunol.0803590.Search in Google Scholar PubMed
14. Riley, EP, McGee, CL. Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med 2005;230:357–65. https://doi.org/10.1177/15353702-0323006-03.Search in Google Scholar PubMed
15. Astley, SJ, Aylward, EH, Olson, HC, Kerns, K, Brooks, A, Coggins, TE, et al.. Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders. Alcohol Clin Exp Res 2009;33:1671–89. https://doi.org/10.1007/s11689-009-9004-0.Search in Google Scholar PubMed PubMed Central
16. Norman, AL, Crocker, N, Mattson, SN, Riley, EP. Neuroimaging and fetal alcohol spectrum disorders. Dev Disabil Res Rev 2009;15:209–17. https://doi.org/10.1002/ddrr.72.Search in Google Scholar PubMed PubMed Central
17. Chaudhary, S, Sarkar, DK. Fetal alcohol exposure impairs learning and memory functions and elevates levels of various biochemical markers of Alzheimer’s disease in the brain of twelve-month-old rats. Alcohol Clin Exp Res 2023;47:882–92. https://doi.org/10.1111/acer.15061.Search in Google Scholar PubMed
18. Crews, FT, Lawrimore, CJ, Walter, TJ, Coleman, LGJr. The role of neuroimmune signaling in alcoholism. Neuropharmacology 2017;122:56–73. https://doi.org/10.1016/j.neuropharm.2017.01.031.Search in Google Scholar PubMed PubMed Central
19. Guerri, C, Pascual, M. Impact of neuroimmune activation induced by alcohol or drug abuse on adolescent brain development. Int J Dev Neurosci 2019;77:89–98. https://doi.org/10.1016/j.ijdevneu.2018.11.006.Search in Google Scholar PubMed
20. Lees, B, Meredith, LR, Kirkland, AE, Bryant, BE, Squeglia, LM. Effect of alcohol use on the adolescent brain and behavior. Pharmacol Biochem Behav 2020;192:172906. https://doi.org/10.1016/j.pbb.2020.172906.Search in Google Scholar PubMed PubMed Central
21. Squeglia, LM, Jacobus, J, Tapert, SF. The effect of alcohol use on human adolescent brain structures and systems. Handb Clin Neurol 2014;125:501–10. https://doi.org/10.1016/B978-0-444-62619-6.00028-8.Search in Google Scholar PubMed PubMed Central
23. Ikonomidou, C, Bittigau, P, Ishimaru, MJ, Wozniak, DF, Koch, C, Genz, K, et al.. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrom. Science 2000;287:1056–60. https://doi.org/10.1126/science.287.5455.1056.Search in Google Scholar PubMed
24. Olney, JW, Tenkova, T, Dikranian, K, Qin, YQ, Labruyere, J, Ikonomidou, C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res 2002;133:115–26. https://doi.org/10.1016/s0165-3806(02)00279-1.Search in Google Scholar PubMed
25. Alfonso-Loeches, S, Pascual-Lucas, M, Blanco, AM, Sanchez-Vera, I, Guerri, CJ. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. Neurosciences 2010;30:8285–95. https://doi.org/10.1523/jneurosci.0976-10.2010.Search in Google Scholar PubMed PubMed Central
26. Crews, FT, Bechara, R, Brown, LA, Guidot, DM, Mandrekar, P, Oak, S, et al.. Cytokines and alcohol. Alcohol Clin Exp Res 2006;30:720–30. https://doi.org/10.1111/j.1530-0277.2006.00084.x.Search in Google Scholar PubMed
27. Cherry, JD, Olschowka, JA, O’Banion, MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 2014;11:98. https://doi.org/10.1186/1742-2094-11-98.Search in Google Scholar PubMed PubMed Central
28. Frank-Cannon, TC, Alto, LT, McAlpine, FE, Tansey, MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009;4:47. https://doi.org/10.1186/1750-1326-4-47.Search in Google Scholar PubMed PubMed Central
30. Mukamal, KJ, Kuller, LH, Fitzpatrick, AL, Longstreth, WT, Mittleman, MA, Siscovick, DS. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA 2003;289:1405–13. https://doi.org/10.1001/jama.289.11.1405.Search in Google Scholar PubMed
31. Barnett, A, David, E, Rohlman, A, Nikolova, VD, Moy, SS, Vetreno, RP, et al.. Adolescent binge alcohol enhances early Alzheimer’s disease pathology in adulthood through proinflammatory neuroimmune activation. Front Pharmacol 2022;13:884170. https://doi.org/10.3389/fphar.2022.884170.Search in Google Scholar PubMed PubMed Central
32. Iroegbu, JD, Ijomone, OK, Femi-Akinlosotu, OM, Ijomone, OM. ERK/MAPK signalling in the developing brain: perturbations and consequences. Neurosci Biobehav Rev 2021;131:792–805. https://doi.org/10.1016/j.neubiorev.2021.10.009.Search in Google Scholar PubMed
33. Gouras, GK, Olsson, TT, Hansson, O. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurotherapeutics 2015;12:3–11. https://doi.org/10.1007/s13311-014-0313-y.Search in Google Scholar PubMed PubMed Central
34. Jordà-Siquier, T, Petrel, M, Kouskoff, V, Smailovic, U, Cordelières, F, Frykman, S, et al.. APP accumulates with presynaptic proteins around amyloid plaques: a role for presynaptic mechanisms in Alzheimer’s disease? Alzheimer’s Dement 2022;18:2099–116. https://doi.org/10.1002/alz.12546.Search in Google Scholar PubMed PubMed Central
35. De Strooper, B, Saftig, P, Craessaerts, K, Vanderstichele, H, Guhde, G, Annaert, W, et al.. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391:387–90. https://doi.org/10.1038/34910.Search in Google Scholar PubMed
36. Sherrington, R, Rogaev, EI, Liang, Y, Rogaeva, EA, Levesque, G, Ikeda, M, et al.. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–60. https://doi.org/10.1038/375754a0.Search in Google Scholar PubMed
39. Barbier, P, Zejneli, O, Martinho, M, Lasorsa, A, Belle, V, Smet-Nocca, C, et al.. Role of tau as a microtubule-associated protein: structural and functional aspects. Front Aging Neurosci 2019;11:204. https://doi.org/10.3389/fnagi.2019.00204.Search in Google Scholar PubMed PubMed Central
40. Ferreira, A, Bigio, EH. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med 2011;17:676–85. https://doi.org/10.2119/molmed.2010.00220.Search in Google Scholar PubMed PubMed Central
41. Stewart, CR, Stuart, LM, Wilkinson, K, van Gils, JM, Deng, J, Halle, A, et al.. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155–61. https://doi.org/10.1038/ni.1836.Search in Google Scholar PubMed PubMed Central
42. Liu, Y, Walter, S, Stagi, M, Stagi, M, Cherny, D, Letiembre, M, et al.. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 2005;128:1778–89. https://doi.org/10.1093/brain/awh531.Search in Google Scholar PubMed
43. Bamberger, ME, Harris, ME, McDonald, DR, Husemann, J, Landreth, GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 2003;23:2665–74. https://doi.org/10.1523/jneurosci.23-07-02665.2003.Search in Google Scholar PubMed PubMed Central
44. Paresce, DM, Ghosh, RN, Maxfield, FR. Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 1996;17:553–65. https://doi.org/10.1016/s0896-6273(00)80187-7.Search in Google Scholar PubMed
46. Mawuenyega, KG, Sigurdson, W, Ovod, V, Munsell, L, Kasten, T, Morris, JC, et al.. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 2010;330:1774. https://doi.org/10.1126/science.1197623.Search in Google Scholar PubMed PubMed Central
47. Liu, Z, Condello, C, Schain, A, Harb, R, Grutzendler, J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. J Neurosci 2010;30:17091–101. https://doi.org/10.1523/jneurosci.4403-10.2010.Search in Google Scholar
48. Nagele, RG, Wegiel, J, Venkataraman, V, Imaki, H, Wang, KC, Wegiel, J. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 2004;25:663–74. https://doi.org/10.1016/j.neurobiolaging.2004.01.007.Search in Google Scholar PubMed
49. Stalder, M, Deller, T, Staufenbiel, M, Jucker, M. 3D-reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid. Neurobiol Aging 2001;22:427–34. https://doi.org/10.1016/s0197-4580(01)00209-3.Search in Google Scholar PubMed
50. Onyango, IG, Jauregui, GV, Čarná, M, Bennett, JPJr, Stokin, GB. Neuroinflammation in Alzheimer’s disease. Biomedicines 2021;9:524. https://doi.org/10.3390/biomedicines9050524.Search in Google Scholar PubMed PubMed Central
51. Spangenberg, EE, Lee, RJ, Najafi, AR, Rice, RA, Elmore, MR, Blurton-Jones, M, et al.. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 2016;139:1265–81. https://doi.org/10.1093/brain/aww016.Search in Google Scholar PubMed PubMed Central
52. Goel, P, Chakrabarti, S, Goel, K, Bhutani, K, Chopra, T, Bali, S. Neuronal cell death mechanisms in Alzheimer’s disease: an insight. Front Mol Neurosci 2022;15:937133. https://doi.org/10.3389/fnmol.2022.937133.Search in Google Scholar PubMed PubMed Central
53. Zhang, L, Qian, Y, Li, J, Zhou, X, Xu, H, Yan, J, et al.. BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer’s disease pathology. Iscience 2021;24:102942. https://doi.org/10.1016/j.isci.2021.102942.Search in Google Scholar PubMed PubMed Central
54. Sil, S, Ghosh, T, Ghosh, R. NMDA receptor is involved in neuroinflammation in intracerebroventricular colchicine-injected rats. J Immunotoxicol 2016;13:474–89. https://doi.org/10.3109/1547691x.2015.1130760.Search in Google Scholar
55. Loss, CM, da Rosa, NS, Mestriner, RG, Xavier, LL, Oliveira, DL. Blockade of GluN2B-containing NMDA receptors reduces short-term brain damage induced by early-life status epilepticus. Neurotoxicology 2019;71:138–49. https://doi.org/10.1016/j.neuro.2019.01.002.Search in Google Scholar PubMed
56. Tymianski, M, Charlton, MP, Carlen, PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 1993;13:2085–104. https://doi.org/10.1523/jneurosci.13-05-02085.1993.Search in Google Scholar PubMed PubMed Central
57. Koh, JY, Choi, DW. Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death. Brain Res 1991;548:318–215. https://doi.org/10.1016/0006-8993(91)91140-v.Search in Google Scholar PubMed
58. de la Torre, JC, Mussivand, T. Can disturbed brain microcirculation cause Alzheimer’s disease? Neurol Res 1993;15:146–53. https://doi.org/10.1080/01616412.1993.11740127.Search in Google Scholar PubMed
59. Huang, W, Zhou, H, Hodgkinson, C, Montero, A, Goldman, D, Chang, SL. Network meta-analysis on the mechanisms underlying alcohol augmentation of COVID-19 pathologies. Alcohol Clin Exp Res 2021;45:675–88. https://doi.org/10.1111/acer.14573.Search in Google Scholar PubMed PubMed Central
60. Tabakoff, B, Saba, L, Kechris, K, Hu, W, Bhave, SV, Finn, DA, et al.. The genomic determinants of alcohol preference in mice. Mamm Genome 2008;19:352–65. https://doi.org/10.1007/s00335-008-9115-z.Search in Google Scholar PubMed PubMed Central
61. Krämer, A, Green, J, Pollard, JJr, Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 2014;30:523–30. https://doi.org/10.1093/bioinformatics/btt703.Search in Google Scholar PubMed PubMed Central
62. Green, GH, Diggle, P. On the operational characteristics of the Benjamini and Hochberg false discovery rate procedure. Stat Appl Genet Mol Biol 2007;6:27. https://doi.org/10.2202/1544-6115.1302.Search in Google Scholar PubMed
63. Frautschy, SA, Yang, F, Irrizarry, M, Hyman, B, Saido, TC, Hsiao, K, et al.. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998;152:307–1764.Search in Google Scholar
65. Grimm, MO, Buss, A, Schwaninger, M, Kemmling, A, Schliebs, R. The role of the Bcl-2 family in the regulation of apoptosis in brain aging and neurodegenerative disorders. Biochim Biophys Acta Mol Basis Dis 2002;1592:1–17.Search in Google Scholar
66. Reese, CA, Erisir, A, Testa-Silva, G. BDNF regulates the intrinsic axon growth capacity of developing neurons. J Neurosci 2004;24:10365–73.Search in Google Scholar
67. Yang, P, Arnold, SA, Habas, A, Hetman, M, Hagg, T. Ciliary neurotrophic factor mediates dopamine D2 receptor-induced CNS neurogenesis in adult mice. J Neurosci 2008;28:2231–41. https://doi.org/10.1523/jneurosci.3574-07.2008.Search in Google Scholar
68. Ceccanti, M, Mancinelli, R, Tirassa, P, Laviola, G, Rossi, S, Romeo, M, et al.. Early exposure to ethanol or red wine and long-lasting effects in aged mice. A study on nerve growth factor, brain-derived neurotrophic factor, hepatocyte growth factor, and vascular endothelial growth factor. Neurobiol Aging 2012;33:359–67. https://doi.org/10.1016/j.neurobiolaging.2010.03.005.Search in Google Scholar PubMed
70. Blednov, YA, Benavidez, JM, Black, M, Leiter, CR, Osterndorff-Kahanek, E, Johnson, D, et al.. GABAA receptors containing ρ1 subunits contribute to in vivo effects of ethanol in mice. PLoS One 2014;9:e85525. https://doi.org/10.1371/journal.pone.0085525.Search in Google Scholar PubMed PubMed Central
71. Brentnall, M, Rodriguez-Menocal, L, De Guevara, RL, Cepero, E, Boise, LH. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 2013;14:32. https://doi.org/10.1186/1471-2121-14-32.Search in Google Scholar PubMed PubMed Central
72. Mooney, SM, Miller, MW. Effects of prenatal exposure to ethanol on the expression of bcl-2, bax and caspase 3 in the developing rat cerebral cortex and thalamus. Brain Res 2001;911:71–81. https://doi.org/10.1016/s0006-8993(01)02718-4.Search in Google Scholar PubMed
73. Wang, L, Wu, L, Wang, X, Deng, J, Ma, Z, Fan, W, et al.. Prenatal alcohol exposure inducing the apoptosis of mossy cells in hippocampus of SMS2-/- mice. Environ Toxicol Pharmacol 2015;40:975–82. https://doi.org/10.1016/j.etap.2015.10.004.Search in Google Scholar PubMed
74. Niemi, JP, DeFrancesco-Lisowitz, A, Cregg, JM, Howarth, M, Zigmond, RE. Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. Exp Neurol 2016;275 Pt 1:25–37. https://doi.org/10.1016/j.expneurol.2015.09.018.Search in Google Scholar PubMed PubMed Central
75. Zheng, C, Chen, J, Chu, F, Zhu, J, Jin, T. Inflammatory role of TLR-MyD88 signaling in multiple sclerosis. Front Mol Neurosci 2020;12:314. https://doi.org/10.3389/fnmol.2019.00314.Search in Google Scholar PubMed PubMed Central
76. Pascual, M, Montesinos, J, Montagud-Romero, S, Forteza, J, Rodríguez-Arias, M, Miñarro, J, et al.. TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders. J Neuroinflammation 2017;14:145. https://doi.org/10.1186/s12974-017-0918-2.Search in Google Scholar PubMed PubMed Central
77. Hilliard, A, Mendonca, P, Soliman, KFA. Involvement of NFB and MAPK signaling pathways in the preventive effects of Ganoderma lucidum on the inflammation of BV-2 microglial cells induced by LPS. J Neuroimmunol 2020;345:577269. https://doi.org/10.1016/j.jneuroim.2020.577269.Search in Google Scholar PubMed PubMed Central
78. Wu, BY, Yu, AC. Quercetin inhibits c-fos, heat shock protein, and glial fibrillary acidic protein expression in injured astrocytes. J Neurosci Res 2000;62:730–6. https://doi.org/10.1002/1097-4547(20001201)62:5<730::aid-jnr13>3.0.co;2-k.10.1002/1097-4547(20001201)62:5<730::AID-JNR13>3.0.CO;2-KSearch in Google Scholar
79. Ricchetti, GA, Williams, LM, Foxwell, BM. Heme oxygenase 1 expression induced by IL-10 requires STAT-3 and phosphoinositol-3 kinase and is inhibited by lipopolysaccharide. J Leukoc Biol 2004;76:719–26. https://doi.org/10.1189/jlb.0104046.Search in Google Scholar
80. Casella, G, Garzetti, L, Gatta, AT, Finardi, A, Maiorino, C, Ruffini, F, et al.. IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo. J Neuroinflammation 2016;13:139. https://doi.org/10.1186/s12974-016-0596-5.Search in Google Scholar
81. Sojka, D, Zacharova, G, Spicarova, D, Palecek, J. Changes of calcium binding protein expression in spinothalamic tract neurons after peripheral inflammation. Physiol Res 2010;59:1011–17. https://doi.org/10.33549/physiolres.932063.Search in Google Scholar
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