GENIPOSIDIC ACID CONFERS NEUROPROTECTIVE EFFECTS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE THROUGH ACTIVATION OF A PI3K/AKT/GAP43 REGULATORY AXIS
Q.Y. Chen, Y. Yin, L. Li, Y.J. Zhang, W. He, Y. Shi
J Prev Alz Dis 2022;1(9):158-171
BACKGROUND: Alzheimer’s disease (AD) is a major cause of dementia, which is a growing global health problem and has a huge impact on individuals and society. As the modifying role of geniposidic acid (GPA) has been suggested in AD, this study sets out to determine if and how GPA treatment affects AD progression in mice.
METHODS: Potential downstream target genes of GPA during AD were identified by bioinformatics analysis, revealing GAP43 as a primary candidate protein. Then, mPrP-APPswe/PS1De9 AD transgenic mice were treated with GPA via intragastric administration. This allowed for gain- and loss-of-function assays of candidate proteins being carried out with or without GPA treatment, after which behavioral tests could be conducted for mice. Cortical neuron apoptosis was measured by TUNEL staining, Amyloid β-protein (Aβ) expression in cerebral cortex by Thioflavin-s staining, and Aβ, IL-1β, IL-6, IL-4 and TNF-α levels in cerebral cortex by ELISA. GAP43 expression in cerebral cortex of mice was detected by immunohistochemistry. Primary cortical neurons of embryonic mice were isolated and induced by Aβ1-42 to construct AD cell model. Cell viability was assessed by CCK-8, and axon growth by immunofluorescence.
RESULTS: GPA administration significantly improved the cognitive impairment, reducing Aβ accumulation and neuronal apoptosis in AD mice, and alleviated inflammation and axonal injury of Aβ1-42-induced neurons. GAP43 was shown experimentally to be the target of GPA in AD. Silencing of GAP43 repressed the neuroprotective effect of GPA treatment on AD mice. GPA elevated GAP43 expression via PI3K/AKT pathway activation and ultimately improved nerve injury in AD mice.
CONCLUSION: GPA activates a PI3K/AKT/GAP43 regulatory axis to alleviate AD progression in mice.
Q.Y. Chen ; Y. Yin ; L. Li ; Y.J. Zhang ; W. He ; Y. Shi ; (2021): Geniposidic Acid Confers Neuroprotective Effects in a Mouse Model of Alzheimer’s Disease through Activation of a PI3K/AKT/GAP43 Regulatory Axis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.60