Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Abstract

Background In Alzheimer’s disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. Methods We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aβ1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD + /NADH), and neuroinflammatory factors (IL-1β, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. Results Following Aβ1-40 injury, SA-β-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD + /NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aβ1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1β, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 + BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. Conclusions Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aβ1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy

“…The study of glial senescence in AD has garnered significant interest [ 4 , 25 , 35 , 45 ], especially following the detection of senescent glia accumulations in the brain of P301S transgenic mice in 2018 [ 3 ]. A recent investigation focusing on different tau mouse models highlighted the utility of P301S mice as an effective model for exploring brain cellular senescence, contrasting with the less suitable nature of P301L mice or 3xTg-AD mice [ 5 ].…”

Senescent cells in the brain and where to find them

“…In culture, microglia cells have shown a senescent phenotype, including upregulation of SA‐β‐Gal activity, p16, p21, p53, γH2AX, SAHF, IL‐8, elevated ROS and mitochondrial ROS, as well as downregulation of both Ki‐67 and BrdU (Fig. 1D) [48–54]. These studies suggest that microglia cells can enter a state of cellular senescence in vitro .…”

The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing

“…The phagocytic function of microglia is usually enhanced at an inflammatory activation state [ 177 ] while substantially reduced at the ageing state. Hu et al [ 178 ] reported that Aβ 1-40 induced microglial senescence in vitro. Increased expression of CD38 in ageing microglia is associated with energy metabolism disorder and neuroinflammation.…”