Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: April 26, 2022

Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer's disease (AD). However, mechanisms connecting AD have not been identified. Both and feature proinflammatory signaling. Therefore, we hypothesized adolescent binge ethanol would increase molecular behavioral pathology adulthood through The 3xTg-AD mouse model (APPSwe, tauP301, Psen1tm1Mpm) which features amyloid (Aβ) tau beginning at 6-12 months underwent intermittent (AIE, 5 g/kg/d, i.g., P25-55) assessment of pathologic mediators P200. A second group mice received AIE +/- minocycline (30 mg/kg/d, IP) followed by testing adulthood. Behavioral age included: locomotor activity exploration (27-28 weeks), novel object recognition (NORT, 28-30 3-chamber sociability social memory (29-31 prepulse inhibition (PPI, 30-32 Morris Water Maze reversal (MWM, 31-35 Piezo sleep monitoring (35-37 weeks). We found levels neurotoxic Aβ1-42 adult female hippocampus as well intraneuronal amygdala entorhinal cortex. Phosphorylated residue Thr181 (p-tau-181) was also AIE. Several genes were persistently the hippocampus, including IL-1β, MCP-1, IL-6, IFNα. Expression these strongly correlated p-tau-181 hippocampus. caused persistent decreases (open-field NORT habituation) anxiety-like behavior (thigmotaxis) while reducing retention. Treatment anti-inflammatory compound during blocked increases prevented AIE-induced thigmotaxis loss. Together, data find enhances Blockade signaling exposure prevents ethanol-induced effects on accumulation AD-associated proteins changes relevant to human AD.

Language: Английский

---

Alcohol and stress exposure across the lifespan are key risk factors for Alzheimer's Disease and cognitive decline

Neurobiology of Stress, Journal Year: 2024, Volume and Issue: 29, P. 100605 - 100605

Published: Jan. 4, 2024

Alzheimer's Disease and related dementias (ADRD) are an increasing threat to global health initiatives. Efforts prevent the development of ADRD require understanding behaviors that increase decrease risk neurodegeneration cognitive decline, in addition uncovering underlying biological mechanisms behind these effects. Stress exposure alcohol consumption have both been associated with increased for human populations. However, our ability understand causal requires substantial preclinical research. In this review, we summarize existing animal research investigating connections between lifetime stress exposures ADRD.

Language: Английский

---

Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Feb. 19, 2025

Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer's disease (AD) neuropathology. Both disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated neuroimmune signaling basal forebrain cholinergic neuron degeneration. Adolescent onset binge drinking represents a significant risk for later AUD, accumulating evidence suggests adolescent initiation induces HMGB1 causes degeneration system persists into adulthood. However, it is unknown whether confers increased AD-associated neuropathology through persistent induction signaling. To investigate this question, we first (Experiment 1) assessed in post-mortem human individuals with AUD age relative age-matched moderate controls (CONs). In Experiment 2, treated non-transgenic 5xFAD male female mice, which overexpress both mutant APP PS1, intermittent ethanol (AIE; 5.0 g/kg, i.g. 2-days on/2-days off; postnatal day [P]30 - P55), adult (P100) forebrain. 3, mice received AIE treatment followed by glycyrrhizic acid (150 mg/L), inhibitor, water from P56 P100, tissue was collected on P100 assessment 1), report upregulation Hmgb1 receptors Rage Tlr4 as well microglial activation intraneuronal Aβ1-42 accumulation association reduced marker expression (ChAT). mouse model 2), accelerated genes, activation, reductions ChAT+ neurons female, but not male, post-AIE rescued AIE-induced acceleration increases signaling, mice. Together, these findings exposure represent underappreciated adulthood HMGB1- mediated

Language: Английский

---

Impact of Neuroimmune System Activation by Adolescent Binge Alcohol Exposure on Adult Neurobiology

Advances in experimental medicine and biology, Journal Year: 2025, Volume and Issue: unknown, P. 179 - 208

Published: Jan. 1, 2025

Language: Английский

---

Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation

Cells, Journal Year: 2021, Volume and Issue: 10(12), P. 3323 - 3323

Published: Nov. 26, 2021

High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is “damage-associated molecular pattern” molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 an oxidation-reduction sensitive DAMP bearing three cysteines, the post-translational modification of these residues establishes its proinflammatory anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms also occupy important niche immunity because may carry other DAMPs pathogen-associated pattern molecules (PAMPs). with DAMP/PAMP cofactors bind receptor for advanced glycation end products (RAGE) which internalizes complexes endocytosis incorporation lysosomal compartments. Intra-lysosomal disrupts membranes thereby releasing HMGB1-transported stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed development HMGB1-binding antagonists diagnostic or therapeutic use. However, recent discoveries released from neurons mediates inflammation via TLR4 system, cancer cells express fully oxidized as immunosuppressive mechanism, offer new paths targeting inflammation, pain, cancer.

Language: Английский

---

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 10073 - 10073

Published: Sept. 3, 2022

The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This due to existence of neurons secreting various neurotransmitters mutually modulating their own activity through thousands pre- postsynaptic interconnections in each neuron. Astroglial, microglial oligodendroglial cells reciprocally regulate metabolism key energy substrates, thereby exerting several neuroprotective, neurotoxic regulatory effects on neuronal viability neurotransmitter functions. Maintenance pool mitochondrial acetyl-CoA derived from glycolytic glucose a factor for survival. Thus, regarded as direct precursor TCA cycle respiratory chain, affecting cell viability. It also used hundreds acetylation reactions, including N-acetyl aspartate synthesis mitochondria, acetylcholine cholinergic neurons, well divergent acetylations proteins, peptides, histones low-molecular-weight species cellular compartments. Therefore, should be considered central point maintaining equilibrium between anabolic catabolic pathways brain. review presents data supporting this thesis.

Language: Английский

---

Epigenetic regulation of microglia and neurons by proinflammatory signaling following adolescent intermittent ethanol (AIE) exposure and in human AUD

Advances in Drug and Alcohol Research, Journal Year: 2024, Volume and Issue: 4

Published: March 8, 2024

Adolescent alcohol drinking is linked to high rates of adult problems and use disorder (AUD). The Neurobiology Alcohol Drinking in Adulthood (NADIA) consortium adolescent intermittent ethanol (AIE) models binge drinking, followed by abstinent maturation adulthood determine the persistent AIE changes neurobiology behavior. increases preference, anxiety reward seeking, disrupts sleep cognition, all risks for AUD. In addition, induces neuroimmune gene expression neurons glia that alter neurocircuitry HMGB1 a unique signal released from activates multiple proinflammatory receptors, including Toll-like receptors (TLRs), spread induction. increased rat brain post-mortem human AUD brain, where it correlates with lifetime consumption. activation TLR increase expression. Human following show TLRs. Brain regional differences neurotransmitters cell types impact responses Microglia are monocyte-like cells provide trophic synaptic functions, signals sensitize or “prime” during repeated cycles, impacting neurocircuitry. Neurocircuits differently impacted dependent upon neuronal-glial signaling. Acetylcholine an anti-inflammatory neurotransmitter. HMGB1-TLR4 signaling forebrain, reducing cholinergic silencing defining genes through upregulation RE-1 factor (REST), transcription inhibitor known regulate neuronal differentiation. REST induction reduces basal forebrain innervation hippocampus. Adult hippocampal neurogenesis regulated neurogenic niche formed cells. vivo vitro studies find other as well factors, NGF, BDNF, coincident loss synapse marker vChAT. These expression-transcriptomes result reduced neurogenesis. Excitingly, antagonists, anti-inflammatories, epigenetic modifiers like histone deacetylase inhibitors restore findings suggest drugs should be considered therapy may long-lasting reversal psychopathology.

Language: Английский

---

Alcohol, HMGB1, and Innate Immune Signaling in the Brain

Alcohol research, Journal Year: 2024, Volume and Issue: 44(1)

Published: Jan. 1, 2024

Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases and alcohol-related problems that develop into compulsive use the chronic relapsing disease, disorder (AUD). Over past decade, neuroimmune signaling has been discovered contribute alcohol-induced changes drinking, mood, neurodegeneration. This review presents mechanistic hypothesis supporting high mobility group box protein 1 (HMGB1) Toll-like receptor (TLR) as key elements across glia neurons, which shifts gene transcription synapses, altering neuronal networks development AUD. may help guide further research on prevention treatment.

Language: Английский

---

The role of sex in the persistent effects of adolescent alcohol exposure on behavior and neurobiology in rodents

International review of neurobiology, Journal Year: 2021, Volume and Issue: unknown, P. 305 - 340

Published: Jan. 1, 2021

Language: Английский

---

Chronic Ethanol Causes Persistent Increases in Alzheimer’s Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment

Frontiers in Behavioral Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: May 11, 2022

Epidemiological studies have found that heavy alcohol use is associated with increased risk for Alzheimer's disease (AD), frequent drinking earlier in adulthood increasing risk. The increases neuroinflammation featured both and AD may be partially responsible this link. However, it unknown if abstinence mitigates We hypothesized binge ethanol during mid adult life would persistently increase pathology even after prolonged abstinence. Male female 3xTg-AD mice (APPSwe, tauP301, Psen1tm1Mpm) which feature progressive amyloid (Aβ) tau pathology, received chronic (5g/kg/day, 5-days-on/2-days-off, i.g.) or water (from 5.5 to 9 months of age), followed by assessment at 14 age. effects on protective genes (e.g., APOE TREM2) as well proinflammatory were measured PCR. Levels pathologic Aβ immunohistochemistry western blot. Ethanol caused persistent reductions genes: (25% reduction, *p < 0.05), TREM2 (28%, LPL (40%, **p 0.01), CTSD (24%, 0.05) promoted a gene signature female, but not male cortex. Concurrently, total hyperphosphorylated (AT8) piriform cortex hippocampus females, males. AT8 negatively correlated (R = -0.67, -0.78, 0.005) suggesting roles pathogenesis. No differences levels main regulators phosphorylation state (GSK3β, PKA, PP2A), disrupted clearance tau. Therefore, we the effect lysosomes, degrade tau, lysosomal localization using co-immunofluorescence. In reduction mature LAMP1 lysosomes CA1 (35%, along 60% (*p 0.05). Thus, causes enhancement cortical hippocampal brain regions females. Persistent was an lysosomes. This implicates exposure progression

Language: Английский

---