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Carnosic Acid Attenuates AβOs-Induced Apoptosis and Synaptic Impairment via Regulating NMDAR2B and Its Downstream Cascades in SH-SY5Y Cells

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Abstract 

Neuronal death and synaptic loss are principal pathological features of Alzheimer’s disease (AD). Amyloid beta oligomers (AβOs) constitute the main neurotoxin underscoring AD pathology. AβOs interact with N-methyl-D-aspartate receptors (NMDARs), resulting in neurotoxic events, including activation of apoptosis and synaptic impairment. Carnosic acid (CA), extracted from Salvia rosmarinus, has been verified its neuroprotective effects in AD. However, the precise mechanisms by which CA induces synaptic protection remain unclear. In this study, we established an in vitro AD model using SH-SY5Y human neuroblastoma cells. We observed that CA improved neuronal survival by suppressing apoptosis. Moreover, CA restored synaptic impairments by increasing expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and synaptophysin (Syn). Furthermore, we found these protective effects were dependent on inhibiting the phosphorylation of NMDAR subtype 2B (NMDAR2B), which further suppressed calcium overload and promoted activation of the extracellular signal-regulated kinase (ERK)–cAMP response element-binding protein (CREB) pathway. Administration of N-methyl-D-aspartic acid (NMDA), an agonist of NMDARs, abolished these effects of CA. Our findings demonstrate that CA exerts neuroprotective effects in an in vitro model of AD by regulating NMDAR2B and its downstream cascades, highlighting the therapeutic potential of CA as a NMDARs-targeted candidate in the treatment of AD.

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Data Availability

The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

Abbreviations

AD:

Alzheimer’s disease

CA:

Carnosic acid

Aβ:

Amyloid β

AβOs:

Aβ oligomers

NMDA:

N-Methyl-D-aspartic acid

NMDARs:

N-Methyl-D-aspartate receptors

NMDAR2B:

N-Methyl-D-aspartate receptor subtype 2B

ERK:

Extracellular signal-regulated kinase

CREB:

CAMP response element binding protein

BDNF:

Brain-derived neurotrophic factor

Bax:

B cell lymphoma 2 associated X

Bcl-2:

B cell lymphoma 2

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

HBSS:

Hank’s Balanced Salt Solution

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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Acknowledgements

We wish to thank Dr. Di-yang Lyv, Dr. Heng Zhang, Dr. Min Gong, Dr. Xue-chu Wang, Dr. Tan Zhao, and Dr. Yue Zhang for their generous assistant with performing experiments and suggestions on revising the manuscript. We wish to thank Bing-qiu Li, Wen-wen Li, Ya-na Pang, and Mei-na Quan for their guidance.

Funding

This study was supported by the Key Project of the National Natural Science Foundation of China (U20A20354); Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016, Z201100005520017); the National Major R&D projects of China-Scientific Technological Innovation 2030 (2021ZD0201802); the National Key Scientific Instrument and Equipment Development Project (31627803); and the Key Project of the National Natural Science Foundation of China (81530036).

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Authors and Affiliations

  1. Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Changchun Street 45, Xicheng District, Beijing, People’s Republic of China

    Wen-ying Liu, Yan Li, Yan Li, Ling-zhi Xu & Jian-ping Jia

  2. Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, People’s Republic of China

    Yan Li, Ling-zhi Xu & Jian-ping Jia

  3. Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, People’s Republic of China

    Yan Li, Ling-zhi Xu & Jian-ping Jia

  4. Center of Alzheimer’s Disease, Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, People’s Republic of China

    Yan Li, Ling-zhi Xu & Jian-ping Jia

  5. Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, People’s Republic of China

    Yan Li, Ling-zhi Xu & Jian-ping Jia

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  1. Wen-ying Liu
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Jian-ping Jia contributed to the research concept and the study design. Wen-ying Liu designed the study, performed experiments, analyzed data, drew figures, and wrote the manuscript. Yan Li, Yan Li, and Ling-zhi Xu helped with language editing of the manuscript. Jian-ping Jia revised the manuscript critically and obtained funding. All authors contributed to the article and approved the submitted manuscript.

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Liu, Wy., Li, Y., Li, Y. et al. Carnosic Acid Attenuates AβOs-Induced Apoptosis and Synaptic Impairment via Regulating NMDAR2B and Its Downstream Cascades in SH-SY5Y Cells. Mol Neurobiol 60, 133–144 (2023). https://doi.org/10.1007/s12035-022-03032-w

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