Abstract:Anti-RAGE and anti-Abeta IgGs correlate strongly with global scores of dementia. Furthermore, they are associated with a profile of deficiency in domains associated with specific cortical function. Results suggest potential for anti-Abeta and anti-RAGE IgGs as blood biomarkers for AD.
“…Interestingly, ethanol neither impaired behavioral performance nor altered histone activity in TLR4 knockout mice. Another inflammatory pathway, mediated by the RAGE receptor, might be involved in the memory impairments associated with chronic alcohol exposure since neuroinflammation associated with increased expression of this receptor is implicated in the memory impairments that accompany Alzheimer’s disease (Arancio et al, 2004; Fang et al, 2010; Maczurek et al, 2008; Wilson et al, 2009). Adolescent intermittent ethanol treatment of rats has been found to increase expression of RAGE that persists into adulthood and mimics the increase found in post-mortem human alcoholic brain (Vetreno et al, 2013b).…”
Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies.
“…Interestingly, ethanol neither impaired behavioral performance nor altered histone activity in TLR4 knockout mice. Another inflammatory pathway, mediated by the RAGE receptor, might be involved in the memory impairments associated with chronic alcohol exposure since neuroinflammation associated with increased expression of this receptor is implicated in the memory impairments that accompany Alzheimer’s disease (Arancio et al, 2004; Fang et al, 2010; Maczurek et al, 2008; Wilson et al, 2009). Adolescent intermittent ethanol treatment of rats has been found to increase expression of RAGE that persists into adulthood and mimics the increase found in post-mortem human alcoholic brain (Vetreno et al, 2013b).…”
Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies.
“…An additional inflammatory pathway mediated by RAGE might also contribute to addiction and the cognitive impairments associated with alcoholism. Studies in the postmortem human alcoholic brain and AIE model find increased expression of RAGE in the adult prefrontal cortex (Vetreno et al 2013), and this receptor has been implicated in memory impairments associated with Alzheimer’s disease (Arancio et al 2004; Fang et al 2010; Maczurek et al 2008; Wilson et al 2009). Together, these data connect TLRs, RAGE, HMGB1, and other innate immune signaling molecules with epigenetic modifications to drug- and stress-induced changes in neurobiology that are related to addiction.Fig.…”
Section: Innate Immunity Tlr Signaling and Addictionmentioning
BackgroundAthina Markou and her colleagues discovered persistent changes in adult behavior following adolescent exposure to ethanol or nicotine consistent with increased risk for developing addiction. Building on Dr. Markou’s important work and that of others in the field, researchers at the Bowles Center for Alcohol Studies have found that persistent changes in behavior following adolescent stress or alcohol exposure may be linked to induction of immune signaling in brain.AimThis study aims to illuminate the critical interrelationship of the innate immune system (e.g., toll-like receptors [TLRs], high-mobility group box 1 [HMGB1]) in the neurobiology of addiction.MethodThis study reviews the relevant research regarding the relationship between the innate immune system and addiction.ConclusionEmerging evidence indicates that TLRs in brain, particularly those on microglia, respond to endogenous innate immune agonists such as HMGB1 and microRNAs (miRNAs). Multiple TLRs, HMGB1, and miRNAs are induced in the brain by stress, alcohol, and other drugs of abuse and are increased in the postmortem human alcoholic brain. Enhanced TLR-innate immune signaling in brain leads to epigenetic modifications, alterations in synaptic plasticity, and loss of neuronal cell populations, which contribute to cognitive and emotive dysfunctions. Addiction involves progressive stages of drug binges and intoxication, withdrawal-negative affect, and ultimately compulsive drug use and abuse. Toll-like receptor signaling within cortical-limbic circuits is modified by alcohol and stress in a manner consistent with promoting progression through the stages of addiction.
“…In the CNS, RAGE–mediated inflammatory pathways have been implicated in memory deficits in Alzheimer’s disease (Arancio et al, 2004; Fang et al, 2010; Maczurek et al, 2008; Wilson et al, 2009). Particularly, it has been suggested that RAGE acts as a co-factor for Abeta–induced neuronal perturbation, which ultimately leads to learning and memory abnormalities (Arancio et al, 2004).…”
High-mobility group box-1 (HMGB1) is a nuclear protein with cytokine-type functions upon its extracellular release. HMGB1 activates inflammatory pathways by stimulating multiple receptors, chiefly toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation End Products (RAGE). TLR4 and RAGE activation has been implicated in memory impairments, although the endogenous ligand subserving these effects is unknown. We examined whether HMGB1 induced memory deficits using novel object recognition test, and which of the two receptor pathways was involved in these effects. Non-spatial long-term memory was examined in wild type, TLR4 knockout, and RAGE knockout mice. Recombinant HMGB1 (10 μg, intracerebroventricularly, i.c.v.) disrupted memory encoding equipotently in wild type, TLR4 knockout and RAGE knockout animals, but affected neither memory consolidation, nor retrieval. Neither TLR4 knockout nor RAGE knockout mice per se, exhibited memory deficits. Blockade of TLR4 in RAGE knockout mice using Rhodobacter sphaeroides lipopolysaccharide (LPS-Rs; 20 μg, i.c.v.) prevented the detrimental effect of HMGB1 on memory. These data show that elevated brain levels of HMGB1 induce memory abnormalities which may be mediated by either TLR4, or RAGE. This mechanism may contribute to memory deficits under various neurological and psychiatric conditions associated with the increased HMGB1 levels, such as epilepsy, Alzeheimer’s disease and stroke.
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