Journal Article

Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice

Ou, Zhenri, Zhang, Le, Ye, Xiujuan, Sun, Xiangdong, Long, Dahong, He, Xiaosong, Li, Qingqing, Xuan, Aiguo, Gong, Zhuo, Xu, Liping, Huang, Jingyi, Kong, Xuejian, Lin, Xiaohong, Xu, Biao

2019

Overview

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by an abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and impaired neurogenesis. Urolithin A (UA), a gut-microbial metabolite of ellagic acid, has been reported to exert anti-inflammatory effects in the brain. However, it is unknown whether UA exerts its properties of anti-inflammation and neuronal protection in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD. Methods Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia, Aβ deposition, and neurogenesis. The expression of inflammatory mediators were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The modulating effects of UA on cell signaling pathways were assayed by Western blotting. Results We demonstrated that UA ameliorated cognitive impairment, prevented neuronal apoptosis, and enhanced neurogenesis in APP/PS1 mice. Furthermore, UA attenuated Aβ deposition and peri-plaque microgliosis and astrocytosis in the cortex and hippocampus. We also found that UA affected critical cell signaling pathways, specifically by enhancing cerebral AMPK activation, decreasing the activation of P65NF-κB and P38MAPK, and suppressing Bace1 and APP degradation. Conclusions Our results indicated that UA imparted cognitive protection by protecting neurons from death and triggering neurogenesis via anti-inflammatory signaling in APP/PS1 mice, suggesting that UA might be a promising therapeutic drug to treat AD.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alzheimer Disease - complications / Alzheimer Disease - genetics / Alzheimer's disease / Amyloid / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Animals / Anti-Inflammatory Agents - therapeutic use / Antioxidants / Apoptosis / Biomedical and Life Sciences / Biomedicine / Brain - drug effects / Brain - metabolism / Brain - pathology / Cerebrum / Cognitive ability / Complications and side effects / Coumarins - therapeutic use / Cytokines - genetics / Cytokines - metabolism / Disease Models, Animal / DNA nucleotidylexotransferase / Drug therapy / Ellagic acid / Encephalitis - drug therapy / Encephalitis - etiology / Enzyme-linked immunosorbent assay / Female / Gene Expression Regulation - drug effects / Gene Expression Regulation - genetics / Gliosis / Gliosis - drug therapy / Gliosis - genetics / Health aspects / Immunohistochemistry / Immunology / Inflammation / Intestinal microflora / Kinases / Laboratories / Maze Learning - drug effects / Memory / Memory Disorders - drug therapy / Memory Disorders - etiology / Memory impairment / Memory, Disorders of / Mice / Mice, Inbred C57BL / Mice, Transgenic / Nerve Tissue Proteins - metabolism / Neurobiology / Neurodegenerative diseases / Neurogenesis / Neurogenesis - drug effects / Neurogenesis - genetics / Neuroinflammation / Neurology / Neuronal-glial interactions / Neuropathology / Neurosciences / Plaque, Amyloid - drug therapy / Plaque, Amyloid - etiology / Polymerase chain reaction / Polyphenols / Presenilin 1 / Presenilin-1 - genetics / Presenilin-1 - metabolism / Proteins / Rodents / Senile plaques / Signal transduction / Signal Transduction - drug effects / Signal Transduction - genetics / Transgenic animals / Urolithin A / Western blotting / β-Site APP-cleaving enzyme 1