Sex-Dependent Altered Expression of Cannabinoid Signaling in Hippocampal Astrocytes of the Triple Transgenic Mouse Model of Alzheimer’s Disease: Implications for Controlling Astroglial Activity

Alzheimer’s disease (AD) is a common neurodegenerative disease. In AD-associated neuroinflammation, astrocytes play a key role, finding glial activation both in patients and in animal models. The endocannabinoid system (ECS) is a neurolipid signaling system with anti-inflammatory and neuroprotective properties implicated in AD. Astrocytes respond to external cannabinoid signals and also have their own cannabinoid signaling. Our main objective is to describe the cannabinoid signaling machinery present in hippocampal astrocytes from 3×Tg-AD mice to determine if they are actively involved in the neurodegenerative process. Primary cultures of astrocytes from the hippocampus of 3×Tg-AD and non-Tg offspring were carried out. We analyzed the gene expression of astrogliosis markers, the main components of the ECS and Ca2+ signaling. 3×Tg-AD hippocampal astrocytes show low inflammatory activity (Il1b, Il6, and Gls) and Ca2+ flow (P2rx5 and Mcu), associated with low cannabinoid signaling (Cnr1 and Cnr2). These results were more evident in females. Our study corroborates glial involvement in AD pathology, in which cannabinoid signaling plays an important role. 3×Tg-AD mice born with hippocampal astrocytes with differential gene expression of the ECS associated with an innate attenuation of their activity. In addition, we show that there are sex differences from birth in this AD animal, which should be considered when investigating the pathogenesis of the disease.

[1]  M. Romli,et al.  Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer’s disease: A systematic review and meta-analysis of animal studies , 2023, Frontiers in Pharmacology.

[2]  Cimona V Hinton,et al.  The evolution of cannabinoid receptors in cancer. , 2023, WIREs mechanisms of disease.

[3]  D. Figeys,et al.  Early postnatal defects in neurogenesis in the 3xTg mouse model of Alzheimer’s disease , 2023, Cell Death & Disease.

[4]  L. Hunyady,et al.  Role of the Endocannabinoid System in Metabolic Control Processes and in the Pathogenesis of Metabolic Syndrome: An Update , 2023, Biomedicines.

[5]  Andrew G. Howe,et al.  Revealing the contribution of astrocytes to glutamatergic neuronal transmission , 2023, Frontiers in Cellular Neuroscience.

[6]  G. Marsicano,et al.  Astroglial CB1 receptors, energy metabolism, and gliotransmission: an integrated signaling system? , 2023, Essays in biochemistry.

[7]  Vafa Baradaran Rahimi,et al.  Cannabinoids in neuroinflammatory disorders: Focusing on multiple sclerosis, Parkinsons, and Alzheimers diseases , 2023, BioFactors.

[8]  G. Marsicano,et al.  Endocannabinoid signaling in astrocytes , 2022, Glia.

[9]  A. Gutiérrez,et al.  Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis , 2022, International journal of molecular sciences.

[10]  C. Matute,et al.  Endocannabinoid signaling in brain diseases: Emerging relevance of glial cells , 2022, Glia.

[11]  Surendra Sharma,et al.  Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development , 2022, Pathogens.

[12]  L. Klein-Hitpass,et al.  Regulatory T Cells Contribute to Sexual Dimorphism in Neonatal Hypoxic-Ischemic Brain Injury , 2022, Stroke.

[13]  Huaxi Xu,et al.  Profiling of Sexually Dimorphic Genes in Neural Cells to Identify Eif2s3y, Whose Overexpression Causes Autism-Like Behaviors in Male Mice , 2021, Frontiers in Cell and Developmental Biology.

[14]  J. Suárez,et al.  Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer’s Disease in a Preclinical Model: A Therapeutic Opportunity , 2020, Biology.

[15]  S. Liddelow,et al.  An Overview of Astrocyte Responses in Genetically Induced Alzheimer’s Disease Mouse Models , 2020, Cells.

[16]  S. Reeves,et al.  Endocannabinoid system alterations in Alzheimer’s disease: A systematic review of human studies , 2020, Brain Research.

[17]  J. Argente,et al.  Maternal hypercaloric diet affects factors involved in lipid metabolism and the endogenous cannabinoid systems in the hypothalamus of adult offspring: sex-specific response of astrocytes to palmitic acid and anandamide , 2020, Nutritional neuroscience.

[18]  P. Piazza,et al.  Glucose metabolism links astroglial mitochondria to cannabinoid effects , 2020, Nature.

[19]  L. Ferraro,et al.  Astrocytic palmitoylethanolamide pre-exposure exerts neuroprotective effects in astrocyte-neuron co-cultures from a triple transgenic mouse model of Alzheimer's disease. , 2020, Life sciences.

[20]  T. Bisogno,et al.  Cannabinoids and the expanded endocannabinoid system in neurological disorders , 2019, Nature Reviews Neurology.

[21]  H. Boutin,et al.  In vivo molecular imaging of neuroinflammation in Alzheimer's disease , 2018, Journal of neurochemistry.

[22]  T. Saido,et al.  Neuroinflammation in mouse models of Alzheimer's disease , 2018, Clinical & experimental neuroimmunology.

[23]  V. Marzo.  New approaches and challenges to targeting the endocannabinoid system , 2018, Nature Reviews Drug Discovery.

[24]  Zhaojun Wang,et al.  Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer’s Disease , 2018, Neuroscience Bulletin.

[25]  M. Sastre,et al.  In vivo Imaging of Glial Activation in Alzheimer's Disease , 2018, Front. Neurol..

[26]  Gabriel A. Devenyi,et al.  Early-in-life neuroanatomical and behavioural trajectories in a triple transgenic model of Alzheimer’s disease , 2018, Brain Structure and Function.

[27]  C. Diéguez,et al.  Cooperative role of the glucagon‐like peptide‐1 receptor and β3‐adrenergic‐mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats , 2018, Acta physiologica.

[28]  Yue-Ming Li,et al.  The role of astrocytes in amyloid production and Alzheimer's disease , 2017, Open Biology.

[29]  J. Berwick,et al.  Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease , 2017, Neuropathology and applied neurobiology.

[30]  E. Galea,et al.  Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease , 2017, Glia.

[31]  M. Fakhoury.  Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy , 2017, Current neuropharmacology.

[32]  A. Romano,et al.  Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target , 2017, Front. Neurosci..

[33]  U. Sengupta,et al.  Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases , 2016, Journal of Alzheimer's disease : JAD.

[34]  E. Hol,et al.  Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease , 2016, Progress in Neurobiology.

[35]  B. Hyman,et al.  3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice , 2016, PloS one.

[36]  A. Verkhratsky,et al.  Astrocytes in physiological aging and Alzheimer’s disease , 2016, Neuroscience.

[37]  J. Argente,et al.  Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes , 2016, Scientific Reports.

[38]  Eric Karran,et al.  The Cellular Phase of Alzheimer’s Disease , 2016, Cell.

[39]  A. Verkhratsky,et al.  Astroglia dynamics in ageing and Alzheimer's disease. , 2016, Current opinion in pharmacology.

[40]  Hemant R. Jadhav,et al.  Reactive Astrogliosis: Role in Alzheimer's Disease. , 2015, CNS & neurological disorders drug targets.

[41]  E. Obrador,et al.  WIN 55,212-2, Agonist of Cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture , 2015, PloS one.

[42]  J. Satoh,et al.  Human Astrocytes: Secretome Profiles of Cytokines and Chemokines , 2014, PloS one.

[43]  A. Pastor,et al.  Analysis of ECs and related compounds in plasma: artifactual isomerization and ex vivo enzymatic generation of 2-MGs[S] , 2014, Journal of Lipid Research.

[44]  Blaine R. Roberts,et al.  The Role of Aβ in Alzheimer's Disease , 2013 .

[45]  K. Manaye,et al.  Distribution patterns of cannabinoid CB1 receptors in the hippocampus of APPswe/PS1ΔE9 double transgenic mice , 2011, Brain Research.

[46]  P. Grant,et al.  Sex differences in histone modifications in the neonatal mouse brain , 2009, Epigenetics.

[47]  D. Praticò,et al.  Evidence of Oxidative Stress in Alzheimer's Disease Brain and Antioxidant Therapy , 2008, Annals of the New York Academy of Sciences.

[48]  D. Centonze,et al.  The endocannabinoid system in targeting inflammatory neurodegenerative diseases. , 2007, Trends in pharmacological sciences.

[49]  Michael T. Heneka,et al.  Inflammatory processes in Alzheimer's disease , 2007, Journal of Neuroimmunology.

[50]  T. Klein.  Cannabinoid-based drugs as anti-inflammatory therapeutics , 2005, Nature Reviews Immunology.

[51]  Alberto Rábano,et al.  Cannabinoid CB2 Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer's Disease Brains , 2003, The Journal of Neuroscience.

[52]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[53]  Tony Wyss-Coray,et al.  Inflammation in Neurodegenerative Disease—A Double-Edged Sword , 2002, Neuron.

[54]  J. Glowinski,et al.  Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes , 1995, Nature.

[55]  S. Kaur,et al.  Cells , 2019, Tissue Engineering in Oral and Maxillofacial Surgery.

[56]  J. Marcu,et al.  Molecular Pharmacology of CB1 and CB2 Cannabinoid Receptors , 2016 .

[57]  K. Mackie,et al.  Distribution of the Endocannabinoid System in the Central Nervous System. , 2015, Handbook of experimental pharmacology.

[58]  G. Bedse,et al.  Altered expression of the CB1 cannabinoid receptor in the triple transgenic mouse model of Alzheimer's disease. , 2014, Journal of Alzheimer's disease : JAD.

[59]  P. Mcgeer,et al.  Alzheimer disease and neuroinflammation. , 2000, Journal of neural transmission. Supplementum.

[60]  V. Di Marzo.  'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. , 1998, Biochimica et biophysica acta.