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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Aβ promotes CD38 expression in senescent microglia in Alzheimer's disease
Yiran Hu1, Yan Huang2, Sanli Xing3
1Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 200031, China.
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.
Insights
Targeting CD38 in Alzheimer's disease (AD) improves microglial energy metabolism and reduces neuroinflammation. This study shows CD38 inhibition alleviates AD pathology and cognitive deficits in mice.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Alzheimer's disease (AD) is linked to neuroinflammation from senescent microglia and energy metabolism issues.
- The precise mechanisms connecting aging microglia's energy metabolism and neuroinflammation in AD are not fully understood.
Purpose of the Study:
- To investigate the role of CD38 in the interplay between microglial senescence, energy metabolism, and neuroinflammation in Alzheimer's disease.
- To evaluate the therapeutic potential of targeting CD38 in AD models.
Main Methods:
- Utilized BV2 microglial cells and AD model mice (APP/PS1).
- Employed biochemical assays, ELISA, immunofluorescence, western blot, and behavioral tests.
- Assessed effects of CD38 knockdown and CD38 inhibitor on cellular and animal models.
Main Results:
- Aβ1-40 induced microglial senescence, impaired energy metabolism, and increased inflammatory markers in BV2 cells.
- CD38 knockdown in BV2 cells ameliorated energy dysmetabolism and reduced neuroinflammation.
- In AD mice, CD38 inhibition decreased amyloid plaques, improved microglial function, restored energy metabolism, reduced inflammation, and enhanced cognitive function.
Conclusions:
- Senescent microglia and increased CD38 expression contribute to energy metabolism disorder in AD.
- Reducing CD38 expression effectively improves energy metabolism and mitigates neuroinflammation.
- CD38 inhibition shows therapeutic promise for Alzheimer's disease by addressing metabolic and inflammatory pathways.
