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Canna~Fangled Abstracts

Alterations of endocannabinoid signaling and microglia reactivity in the retinas of AD-like mice precede the onset of hippocampal β-amyloid plaques

By November 18, 2024No Comments

. 2024 Nov 18.

doi: 10.1111/jnc.16256.

Online ahead of print.
Annamaria Tisi 1, Lucia Scipioni 1 2, Giulia Carozza 1, Lucia Di Re 1, Giacomo Cimino 1, Camilla Di Meo 1 3, Sakthimala Palaniappan 1, Francesco Della Valle 4, Federico Fanti 4, Giacomo Giacovazzo 2 3, Dario Compagnone 4, Rita Maccarone 1, Sergio Oddi 2 3, Mauro Maccarrone 1 2
Affiliations 

Abstract

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 (CB2) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2-arachidonoylglycerol (2-AG), in TG retinas. Fluorescence intensity analysis of anti-CB2 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 CB2 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 CB2, MAGL and 2-AG-occur in the retina of AD-like mice before retinal degeneration and development of hippocampal β-amyloid plaques.

Keywords: Alzheimer’s disease, bioactive lipids, endocannabinoids, neuroinflammation, retina

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References

REFERENCES

    1. Albarracin, R., Natoli, R., Rutar, M., Valter, K., & Provis, J. (2013). 670 nm light mitigates oxygen‐induced degeneration in C57BL/6J mouse retina. BMC Neuroscience, 14, 125.
    1. Alzheimer’s association. (2021). 2021 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17(3), 327‐406.
    1. Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., Ferretti, V., Reverte, I., Sanchini, C., Marrone, M. C., Giubettini, M., De Turris, V., Salerno, D., Garofalo, S., St‐Pierre, M. K., Carrier, M., Renzi, M., Pagani, F., Modi, B., … Ragozzino, D. (2022). Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia, 70(1), 173–195.
    1. Basilico, B., Pagani, F., Grimaldi, A., Cortese, B., Di Angelantonio, S., Weinhard, L., Gross, C., Limatola, C., Maggi, L., & Ragozzino, D. (2019). Microglia shape presynaptic properties at developing glutamatergic synapses. Glia, 67(1), 53–67.
    1. Benito, C., Núñez, E., Tolón, R. M., Carrier, E. J., Rábano, A., Hillard, C. J., & Romero, J. (2003). Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque‐associated glia in Alzheimer’s disease brains. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(35), 11136–11141.

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