Aβ Chronic Exposure Promotes an Activation State of Microglia through Endocannabinoid Signalling Imbalance.
Lucia ScipioniDaniel TortolaniFrancesca CiaramellanoFederico FantiThais GazziManuel SergiMarc NazaréSergio OddiMauro MaccarronePublished in: International journal of molecular sciences (2023)
Dysfunctional phenotype of microglia, the primary brain immune cells, may aggravate Alzheimer's disease (AD) pathogenesis by releasing proinflammatory factors, such as nitric oxide (NO). The endocannabinoids N -arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids increasingly recognised for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. To investigate the possible impact of chronic exposure to β-amyloid peptides (Aβ) on the microglial endocannabinoid signalling, we characterised the functional expression of the endocannabinoid system on neonatal microglia isolated from wild-type and Tg2576 mice, an AD-like model, which overexpresses Aβ peptides in the developing brain. We found that Aβ-exposed microglia produced 2-fold more 2-AG than normal microglia. Accordingly, the expression levels of diacylglycerol lipase-α (DAGLα) and monoacylglycerol lipase (MAGL), the main enzymes responsible for synthesising and hydrolysing 2-AG, respectively, were consistently modified in Tg2576 microglia. Furthermore, compared to wild-type cells, transgenic microglia basally showed increased expression of the cannabinoid 2 receptor, typically upregulated in an activated proinflammatory phenotype. Indeed, following inflammatory stimulus, Aβ-exposed microglia displayed an enhanced production of NO, which was abolished by pharmacological inhibition of DAGLα. These findings suggested that exposure to Aβ polarises microglial cells towards a pro-AD phenotype, possibly by enhancing 2-AG signalling.
Keyphrases
- inflammatory response
- neuropathic pain
- wild type
- lipopolysaccharide induced
- poor prognosis
- lps induced
- nitric oxide
- induced apoptosis
- quantum dots
- spinal cord injury
- highly efficient
- white matter
- oxidative stress
- resting state
- binding protein
- metabolic syndrome
- long non coding rna
- insulin resistance
- multiple sclerosis
- adipose tissue
- amino acid
- signaling pathway
- cerebral ischemia
- hydrogen peroxide