Biology subjects

Vetreno, R.

Publications and source records attributed to Vetreno, R..

3 recordsLinked to original sources

bioRxiv2025

Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder

Reactive microglia are associated with multiple brain diseases that may have specific disease phenotypes. Studies of human cortical microglia in alcohol use disorder (AUD) have characterized reactive microglial subtypes by transcriptome or histology. Preclinical studies have found proinflammatory signaling and microglia contribute to increases in alcohol drinking and preference, behaviors unique to AUD. This study of post-mortem human AUD combines microglial immunoreactivity (+IR) protein and changes in microglial gene expression (mRNA) in human orbital frontal cortex (OFC) in an effort to better characterize the reactive microglia associated with AUD. Since reactive microglia are linked to reactive astrocytes (GFAP+IR), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG+IR), and neurodegeneration (NeuN, MAP2+IR), we assessed these markers within the OFC. AUD reactive microglia were identified by increases in Iba1, CD11b (Mac1-OX42), CX3CR1, CSF1R, CD68, CCR2, P2RY12, SYK, and TFE3+IR in AUD OFC compared to control moderate drinkers. Tmem119+IR was decreased in AUD brain. Several of these microglial genes had parallel changes in +IR protein and mRNA. However, several microglial markers commonly used to identify reactive microglia did not show changes in mRNA, including Iba1, CD68, P2RY12, and CSF1R+IR. Overall, AUD microglia show increases in monocyte phagocytic markers, but not TREM2, DAP, or complement genes. Reactive microglial markers were highly correlated with reactive astrocyte GFAP+IR, oxidative stress 8-OHdG+IR, and loss of neurons (NeuN, MAP2+IR). Mediation analysis indicated reactive microglia contribute to both reactive astrocytes and oxidative stress, but only reactive astrocytes were found to significantly contribute to loss of neurons (NeuN+IR). These findings are supported by mouse studies finding chronic ethanol exposure increases reactive astrocytes and oxidative stress that is inhibited by DREADD blockade of microglial activation. Our findings support a distinct AUD reactive microglial phenotype that activates astrocytes, contributing to AUD neurodegeneration and possibly heavy drinking.

pharmacology and toxicology↗

bioRxiv2025

Adolescent Binge Ethanol Exposure Confers Lasting Alcohol Tolerance across a Cumulative Ethanol Challenge in Adulthood: Involvement of Proinflammatory HMGB1 Signaling

BackgroundEpidemiological studies suggest heavy adolescent binge drinking is strongly associated with later development of an alcohol use disorder (AUD). Alcohol tolerance (i.e., an acquired reduction in acute alcohol responsivity) is a universally recognized symptom of AUD, but the direct contribution of adolescent binge drinking to adult alcohol tolerance is poorly understood. Methods and MaterialsTo investigate the contributions of adolescent binge ethanol exposure to lasting acquisition of acute tolerance, we used our ethanol response battery (ERB) to assess intoxication rating, hypothermia, motor coordination, and balance across cumulative ethanol doses (i.e., 0.0, 0.5, 1.0, 2.0, and 3.0 g/kg) in adult female Wistar rats following adolescent intermittent ethanol (AIE), lipopolysaccharide (LPS), and glycyrrhizic acid treatment following AIE. ResultsWe report AIE, which models human adolescent binge drinking, confers lasting alcohol tolerance across cumulative ethanol doses and blunts ethanol-induced increases in proinflammatory HMGB1 plasma levels. Adolescent LPS (1.0 mg/kg, i.p.) treatment, which mimics AIE-induced HMGB1-mediated neuroinflammation, induces adult alcohol tolerance and blunts HMGB1 release across cumulative ethanol doses on the ERB. Assessment of proinflammatory HMGB1 involvement in AIE-induced acquisition of lasting alcohol tolerance revealed that post-AIE administration of the HMGB1 inhibitor glycyrrhizic acid reversed the AIE-induced acquisition of alcohol tolerance in adulthood. ConclusionsThese data reveal that (1) adolescent binge drinking confers long-lasting low ethanol responsivity, (2) proinflammatory neuroimmune activation contributes to the development of alcohol tolerance, and (3) blockade of proinflammatory HMGB1 signaling reverses AIE-induced acquisition of alcohol tolerance in adulthood. These findings suggest a potential mechanistic target for the development of novel therapeutics for the treatment of AUD.

neuroscience↗

bioRxiv2024

Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease

Underlying drivers of late-onset Alzheimers disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed A{beta} localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal A{beta}. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with A{beta}1-42, and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of A{beta} in neuronal lysosomes to drive AD amyloid pathology. SummaryCellular and molecular drivers of late-onset Alzheimers disease (LOAD) are unknown, though several risk factors account for the majority of disease incidence1-5. Though diverse in their biological natures, each of these risk exposures converge on a shared pathological progression with the accumulation of amyloid early in the disease. Human genetic and transcriptomic studies suggest a role for altered lipid metabolism6-9, though the mechanism has been unknown. Here, using two common midlife risk exposures for LOAD, we found that dysfunctional lipophagy caused by the loss of lysosomal acid lipase (LAL) promotes early LOAD pathogenesis. Both midlife obesity and heavy alcohol reduced neuronal LAL, causing an increase in neuronal lysosomal lipid, and a subsequent accumulation of A{beta} in the extra-lysosomal cytosol. This loss of LAL preceded and promoted A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented increases in amyloid and improved cognition. In human brain, LAL declined with age in healthy subjects, similar to rodents, showing robust losses in LOAD subjects with polymerase pausing. Together, this implicates neuronal LAL loss in LOAD pathogenesis and presents LAL as a promising diagnostic, preventative, and/or therapeutic target for AD.

neuroscience↗