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Extra-cerebral manifestations of Alzheimer's disease (AD) develop in the retina, which is, therefore, considered a "window to the brain". Recent studies demonstrated the dysregulation of the endocannabinoid (eCB) system (ECS) in AD brain. Here, we explored the possible alterations of ECS and the onset of gliosis in the retina of AD-like mice. Tg2576 (TG) mice overexpressing the amyloid precursor protein (APP) were used at the age of 12 months, when hippocampal β-amyloid plaques had not been developed yet. Analysis of retinal gliosis showed a significant increase in the number of IBA1 (+) microglia cells in TG versus wild type (WT). Gliosis was not associated with retinal β-amyloid plaques, evident retinal degenerative signatures, or excitotoxicity; instead, oxidative stress burden was observed as increased acrolein levels. Analysis of the ECS (receptors/metabolic enzymes) through western blotting (WB) revealed the up-regulation of cannabinoid receptor 2 (CB 2 ) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2-arachidonoylglycerol (2-AG), in TG retinas. Fluorescence intensity analysis of anti-CB 2 and anti-MAGL immuno-stained cryosections was consistent with WB, showing their up-regulation throughout the retinal layers. No statistically significant differences were found for the other enzymes/receptors of the ECS under study. However, linear regression analysis for individual animals showed a significant correlation between CB 2 and fatty acid amide hydrolase (FAAH), diacylglycerol lipase α/β (DAGLα/β), and APP; instead, a significant negative correlation was found between MAGL and APP. Finally, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) demonstrated a significant reduction of 2-AG in TG retinas (~0.34 ng/mg) compared to WT (~1.70 ng/mg), while a trend toward increase was found for the other eCB anandamide (AEA). Overall, our data indicate that gliosis and ECS dysregulation-in particular of CB 2 , MAGL and 2-AG-occur in the retina of AD-like mice before retinal degeneration and development of hippocampal β-amyloid plaques., (© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Study Design: Retrospective study., Objectives: To check the hypothesis that irisin could mediate systemic metabolic effects of testosterone in men with chronic spinal cord injury (SCI)., Setting: Spinal Unit of the San Raffaele Institute in Sulmona., Methods: Fifteen men with chronic SCI admitted to a rehabilitation program were involved. They underwent clinical and biochemical evaluations. Irisin levels were measured with a high-sensitivity ELISA kit. Free testosterone levels were calculated (cFT) from total testosterone, sex hormone binding globulin, and albumin concentrations using the Vermeulen formula., Results: Androgen deficiency (total testosterone <3 ng/ml and cFT <64 pg/ml) was found in 53% of participants and was associated with significantly lower irisin levels, higher body mass index (BMI), and higher triglycerides. Participants were engaged in significantly poorer leisure time physical activity (LTPA). Circulating irisin correlated with cFT (r = 0.55; p = 0.03) and both were negatively correlated with triglycerides levels, homeostatic model assessment of insulin resistance (HOMA-IR) and systemic inflammation, as assessed by erythrocyte sedimentation rate (ESR). Correlations with irisin did not reach statistical significance for either BMI (r = -0.40; p = 0.13) or LTPA (r = 0.46; p = 0.08). In bivariate linear regression models, lower irisin levels were significantly associated with higher triglycerides (β = -0.46; 95% CI: -0.75 to -0.16), HOMA-IR (β = -0.32; 95% CI: -0.63 to -0.004) and ESR (β = -0.89; 95% CI: -1.69 to -0.10) independently of cFT. Conversely, the negative associations of cFT with the same variables were lost after adjustment for irisin levels., Conclusions: Spinal cord-injured men with androgen deficiency exhibit lower levels of irisin, which could mediate the systemic effects of testosterone., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: The study was approved by the Ethics Committee of L’Aquila and Teramo provinces, Italy (Approval Code: 11/CE/15 of May 7, 2015)., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer's disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis (APP/PS1 and Tg2576). Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inhibition robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis and provide proof of concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD., (© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

In this study, we employed a novel fluorescent probe, RO7304924-which selectively targets cannabinoid 2 receptor (CB2R)-to assess the lateral mobility of CB2R within the plasma membrane of Chinese hamster ovary cells stably expressing a functional, untagged receptor variant. Utilizing confocal fluorescence recovery after photobleaching (FRAP), we quantified the diffusion coefficient and mobile fraction of CB2R, thereby demonstrating the efficacy of RO7304924 as an innovative tool for elucidating the dynamics of this major endocannabinoid-binding G protein-coupled receptor. Our present findings highlight the potential of combining advanced ligand-based fluorescent probes with FRAP for future investigations into the biochemical details of CB2R mobility in living cells, and its impact on receptor-dependent cellular processes., (© 2025 Wiley‐VCH GmbH.)

Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide-inflamed human keratinocytes (HaCaT cells). CBN was found to increase the expression of cannabinoid receptor 1 (CB 1 ) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2-arachidonoylglicerol (2-AG), by increasing the activities of N-acyl phosphatidylethanolamines-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH)-the biosynthetic and degradative enzyme of AEA-and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2-AG. CBN also affected keratinocyte inflammation by reducing the release of pro-inflammatory interleukin (IL)-8, IL-12, and IL-31 and increasing the release of anti-inflammatory IL-10. Of note, the release of IL-31 was mediated by TRPV1. Finally, the mitogen-activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS-directed drugs. Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti-inflammatory effects-remarkably via TRPV1-in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes., (© 2024 The Author(s). BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)