PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury

Josephin Wagner; Lauren M Park; Partha Mukhopadhyay; Csaba Matyas; Eszter Trojnar; Ruslan Damadzic; Jeesun Jung; Andrew S Bell; Lucas A Mavromatis; Ali M Hamandi; Daniel B Rosoff; Leandro F Vendruscolo; George F Koob; Pal Pacher; Falk W Lohoff

doi:10.1016/j.bbi.2024.04.022

PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury

Brain Behav Immun. 2024 Apr 22:119:494-506. doi: 10.1016/j.bbi.2024.04.022. Online ahead of print.

Authors

Affiliations

¹ Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.
² Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, United States.
³ Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.
⁴ Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States; Department of Medicine, NYU Grossman School of Medicine, New York, New York, United States.
⁵ Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States; NIH-Oxford-Cambridge Scholars Program, Radcliffe Department of Medicine, University of Oxford, UK.
⁶ Stress and Addiction Neuroscience Unit, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, United States.
⁷ Neurobiology of Addiction Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States.
⁸ Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States. Electronic address: falk.lohoff@nih.gov.

PMID: 38657842
DOI: 10.1016/j.bbi.2024.04.022

Abstract

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

Keywords: AUD; Alirocumab; BBB; Cellular injury; LDL-C; LDLR; Oxidative stress; PCSK9.