Alcohol-Related Brain Damage in Humans (original) (raw)
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Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin b II, and aand b-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in a-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in b-spectrin protein levels, and a significant increase in transmembranous a3 (catalytic) subunit of the Na + ,K + -ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of a-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic aand b-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.
Brain sciences, 2018
Repetitive excessive alcohol intoxication leads to neuronal damage and brain shrinkage. We examined cytoskeletal protein expression in human tissue from Brodmann's area 9 of the prefrontal cortex (PFC). Brain samples from 44 individuals were divided into equal groups of 11 control, 11 alcoholic, 11 non-alcoholic suicides, and 11 suicide alcoholics matched for age, sex, and delay. Tissue from alcoholic cohorts displayed significantly reduced expression of α- and β-tubulins, and increased levels of acetylated α-tubulin. Protein levels of histone deacetylase-6 (HDAC6), and the microtubule-associated proteins MAP-2 and MAP-tau were reduced in alcoholic cohorts, although for MAPs this was not significant. Tubulin gene expressions increased in alcoholic cohorts but not significantly. Brains from rats administered alcohol for 4 weeks also displayed significantly reduced tubulin protein levels and increased α-tubulin acetylation. PFC tissue from control subjects had reduced tubulin prot...
Synaptic proteome changes in the superior frontal gyrus and occipital cortex of the alcoholic brain
PROTEOMICS - CLINICAL APPLICATIONS, 2009
Cognitive deficits and behavioral changes that result from chronic alcohol abuse are a consequence of neuropathological changes which alter signal transmission through the neural network. To focus on the changes that occur at the point of connection between the neural network cells, synaptosomal preparations from post-mortem human brain of six chronic alcoholics and six non-alcoholic controls were compared using 2D-DIGE. Functionally affected and spared regions (superior frontal gyrus, SFG, and occipital cortex, OC, respectively) were analyzed from both groups to further investigate the specific pathological response that alcoholism has on the brain. Forty-nine proteins were differentially regulated between the SFG of alcoholics and the SFG of controls and 94 proteins were regulated in the OC with an overlap of 23 proteins. Additionally, the SFG was compared to the OC within each group (alcoholics or controls) to identify region specific differences. A selection were identified by MALDI-TOF mass spectrometry revealing proteins involved in vesicle transport, metabolism, folding and trafficking, and signal transduction, all of which have the potential to influence synaptic activity. A number of proteins identified in this study have been previously related to alcoholism; however, the focus on synaptic proteins has also uncovered novel alcoholism-affected proteins. Further exploration of these proteins will illuminate the mechanisms altering synaptic plasticity, and thus neuronal signaling and response, in the alcoholic brain.
Genes and gene expression in the brain of the alcoholic
Addictive Behaviors, 2004
Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABA A receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and g-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-D-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABA A receptor h subunit mRNA expression, and GABB2 and DRD2B genotypes with h subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence.
Pharmacology Biochemistry and Behavior, 2011
Despite extensive description of the damaging effects of chronic alcohol exposure on brain structure, mechanistic explanations for the observed changes are just emerging. To investigate regional brain changes in protein expression levels following chronic ethanol treatment, one rat per sibling pair of male Wistar rats was exposed to intermittent (14 hr/day) vaporized ethanol, the other to air for 26 weeks. At the end of 24 weeks of vapor exposure, the ethanol group had blood ethanol levels averaging 450 mg %, had not experienced a protracted (>16 hr) withdrawal from ethanol, and revealed only mild evidence of hepatic steatosis. Extracted brains were microdissected to isolate the prefrontal cortex (PFC), dorsal striatum (STR), corpus callosum genu (CCg), CC body (CCb), anterior vermis (AV), and anterior dorsal lateral cerebellum (ADLC) for protein analysis with two-dimensional gel electrophoresis. Expression levels for 54 protein spots were significantly different between the ethanol-and air-treated groups. Of these 54 proteins, tandem mass spectroscopy successfully identified 39 unique proteins, the levels of which were modified by ethanol treatment: 13 in the PFC, 7 in the STR, 2 in the CCg, 7 in the CCb, 7 in the AV, and 5 in the ADLC. The functions of the proteins altered by chronic ethanol exposure were predominately associated with neurotransmitter systems in the PFC and cell metabolism in the STR. Stress response proteins were elevated only in the PFC, AV, and ADLC perhaps supporting a role for frontocerebellar circuitry disruption in alcoholism. Of the remaining proteins, some had functions associated with cytoskeletal physiology (e.g., in the CCb) and others with transcription/ translation (e.g., in the ADLC). Considered collectively, all but 4 of the 39 proteins identified in the present study have been previously identified in ethanol gene-and/or protein-expression studies lending support for their role in ethanol-related brain alterations.
CNS Drug Reviews, 2006
Studies of alcohol-induced brain damage have clearly indicated that alcohol is neurotoxic. Alcoholics are at increased risk for brain damage from a variety of causes, including poor nutrition, liver disease, and head trauma. Further, alcoholic dementia is the second leading cause of adult dementia in the United States, accounting for approximately 10% of the cases (Alzheimer's disease is the leading cause, accounting for 40 to 60% of cases). A variety of studies report that 50 to 75% of sober, detoxified, long-term alcohol-dependent individuals suffer from some degree of detectable cognitive impairment with approximately 10% suffering from serious dementia. Although more research is required to precisely delineate the effects of alcohol on various types of brain function, there appears to be a continuum of moderate deficits in the majority of long-term alcoholics, progressing to much more severe deficits of Wernicke's disease and Wernicke's encephalopathy with Korsakoff's amnestic syndrome (12,79). A variety of lifestyle factors, including nutrition, are implicated in the more severe cases. However, all of these on the continuum appear to be related to alcohol consumption and to the amount of alcohol consumed. That is, the more severe cases are associated with more severe and chronic longterm alcoholism (12,79). Alcohol-induced changes in the structure of the adult brain have been studied in both humans and rodents. A variety of postmortem histological analyses, as well as supporting imaging analysis, suggest that chronic alcohol changes brain structure. Computed tomography (CT) and magnetic resonance imaging (MRI) studies of human brain have repeatedly shown enlargement of the cerebral ventricles and sulci in most alcoholics. The enlargement of the ventricles and sulci essentially reflects a shrinking of the brain mass. This is consistent with studies on postmortem brain tissue, where alcoholics have a reduction in total brain weight. Particularly severe alcoholics have reductions in the global cerebral hemisphere and cerebellar brain weights that are significantly reduced compared
Genes and Gene Expression in the Brains of Human Alcoholics
Annals of the New York Academy of Sciences, 2006
Chronic alcohol misuse by human subjects leads to neuronal loss in regions such as the superior frontal cortex (SFC). Propensity to alcoholism is associated with several genes. ␥-Aminobutyric acid (GABA) A receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the regional presentation of GABA A and glutamate-NMDA (N-methyl-D-aspartate) receptors in SFC. Autopsy tissue was obtained from alcoholics without comorbid disease, alcoholics with liver cirrhosis, and matched controls. ADH1C, DRD2B, EAAT2, and APOE genotypes modulated GABA A - subunit protein expression in SFC toward a less-effective form of the receptor. Most genotypes did not divide alcoholics and controls on glutamate-NMDA receptor pharmacology, although gender and cirrhosis did. Genotype may affect amino acid transmission locally to influence neuronal vulnerability.
Alcoholism: Clinical & Experimental Research, 2005
This article represents a symposium of the 2004 ISBRA Congress held in Mannheim. The presentations were: Review of the neuropathological and neurochemical changes seen in alcohol-related 'brain shrinkage' by Clive Harper; In Vivo Detection of Macrostructural and Microstructural Markers of Brain Integrity in Human Alcoholism and a Rodent Model of Alcoholism by Adolf Pfefferbaum, Elfar Adalsteinsson and Edith Sullivan; Gene and Protein Changes in the Brains of Alcoholics with 'Brain Shrinkage' by Joanne Lewohl and Peter Dodd; Cross sectional and longitudinal MR spectroscopy studies of chronic adult alcoholics by Michael Taylor; Brain Atrophy Associated with Impairment on a Simulated Gambling Task in Long-Term Abstinent Alcoholics by George Fein and Bennett Landman.
Alcoholism: Clinical and Experimental Research, 2008
Background: Alcoholism is associated with shrinkage of brain tissue and reduction in the number of neurons and dendritic arbors particularly in the prefrontal cortex. These changes correlate with the cognitive defects common in alcoholics. A recent study investigated the mRNA expression of selected genes in the prefrontal cortex and found that the levels of mRNA encoding the neurotrophic factor, midkine (MDK), and the excitatory amino acid transporter 1 (EAAT1) were significantly higher in alcoholics compared with nonalcoholic controls. This study aimed to investigate, whether the transcriptional changes observed result in alterations to protein expression. Additionally, the study aimed to expand our understanding of MDK and EAAT1 action by localizing their expression within morphologically and functionally distinct layers of this brain region.