Introduction: Nicotinamide adenine dinucleotide (NAD + ) is a coenzyme that is central to metabolism and a decline in its level has been connected to endothelial cells (ECs) dysfunction and oxidative stress. Ageing related increase in CD38 expression and activity has been proposed as a key factor in the ageing dependent decline in NAD + level. However, the relative age-dependent changes of CD38 expression in the different brain cells remain unclear. As ageing related cerebrovascular oxidative stress is a critical mechanism for microvascular dysfunction and vascular cognitive impairment, we hypothesized that CD38 will be primarily upregulated in the ECs and perivascular cells in the aged brain. Methods: Brains from aged (18–22 months) and young (3–4 months) male C57BL/6J mice (n=6/group) were examined by western blotting and immunofluorescence (IF) to assess total CD38 expression and its cellular localization. We also measured CD38 enzymatic activity in whole brain homogenate. CD38 colocalization with ECs (CD31), astrocytes (GFAP), microglia (Iba1), neurons (NeuN), and macrophages (CD68) was assessed. Endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule-1 (ICAM-1) were detected by IF as markers of ECs function and activation. Superoxide generation was assessed using dihydroethidium (DHE) staining. Nitric oxide (NO) was measured by 4,5-diaminofluorescein (DAF) staining. Results: Compared to young controls, the aged wild-type mouse brain exhibited 175% higher total CD38 expression (p<0.001) by IF and increased enzymatic activity in brain homogenates by 167% (p=0.029). Co-localization analysis revealed predominant CD38 expression in the ECs, followed by perivascular astrocytes and microglia. Ageing was also associated with a marked reduction in eNOS expression in the brain by 43% (p<0.001) and NO level by 32% (p<0.001). Superoxide generation was increased by 169% (p=0.021), and ICAM-1 expression was increased by 220% (p=0.043) in the ageing brain. Conclusions: The ageing brain exhibits signs of oxidative stress and ECs dysfunction in association with increased CD38 expression mainly within the endothelial and perivascular cells. These findings suggest CD38 as a potential mediator of the ageing dependent cerebrovascular dysfunction and cognitive decline which needs to be investigated in future mechanistic studies.
Ewees et al. (Thu,) studied this question.
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