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Naringenin Upregulates AMPK-Mediated Autophagy to Rescue Neuronal Cells From β-Amyloid (1–42) Evoked Neurotoxicity

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Deposition of an amyloid-β peptide is one of the first events in the pathophysiology of Alzheimer’s disease (AD) and is clinically characterized by Aβ plaques, tau tangles, and behavioral impairments that lead to neuronal death. A substantial number of studies encourage targeting the skewness in the production and degradation of amyloid-β could be among the promising therapies in the disease. Neuronal autophagy has emerged for an essential role in the degradation of such toxic aggregate-prone proteins in various neurodegenerative diseases. We profiled a small library of common dietary compounds and identified those that can enhance autophagy in neuronal cells. Here we noted naringenin in silico exhibits a robust affinity with AMP-activated protein kinase (AMPK) and upregulated AMPK-mediated autophagy signaling in neurons. Naringenin can induce autophagy promoting proteins such as ULK1, Beclin1, ATG5, and ATG7 in Neuro2a cells and primary mouse neurons as well. The knockdown of AMPK by siRNA-AMPK was complemented by naringenin that restored transcript levels of AMPK. Further, naringenin can reduce the levels of Aβ at a nontoxic concentration from neuronal cells. Moreover, it maintained the mitochondrial membrane potential and resisted reactive oxygen species production, which led to the protection against Aβ1–42 evoked neurotoxicity. This highlights the neuroprotective potential of naringenin that can be developed as an anti-amyloidogenic nutraceutical.

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Alzheimer’s disease


AMP-activated protein kinase

MAP 2:

Microtubule-associated protein


Glial fibrillary acidic protein


Microtubule-associated protein 1 light chain 3 beta

mTOR :

Mammalian target of rapamycin

Aβ :

Amyloid beta


Unc-51-like kinase


Autophagy-related protein


Sequestosome 1 protein)




Bafilomycin A1


Tetramethylrhodamine ethyl ester


Thiazolyl blue tetrazolium bromide


Lactate dehydrogenase


5-Aminoimidazole-4-carboxamide ribonucleotide


Mitochondrial membrane potential


Reactive oxygen species


2', 7'-dichloro-dihydro fluorescein diacetate


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We are thankful to UGC (University Grants Commission) for providing financial assistance to Aitizaz Ul Ahsan to carry out this research. We are immensely grateful to Dr. Ajay Kumar for providing his lab during experimental work. We thank Dr. Akeel for his kind help in gifting plasmids. We cannot forget to mention Dr. Abid Hamid for his support and critical suggestions. Thanks are due to Dr. P.R. Sharma for assisting in microscopy and lastly to IIIM, Jammu Kashmir, for keeping facilities available. Dr. Mehak Gupta, Manisha, Mir Faheem Mohammad, Masroor Ahmad, and Adil Qadir, thanks for the help.

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Authors and Affiliations



A.U.A planned and performed the experiments and analyzed the data and compiled the manuscript. A.W. helped in designing some experiments. V.L.S and M.C. revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Mani Chopra.

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The authors declare that they have no competing interests.

Ethical Approval

All animal procedures were approved by the Institutional Animals Ethics Committee IAEC (PU/IAEC/S/15/86), Panjab University Chandigarh.

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• Naringenin confers neuroprotection against soluble Aβ-evoked neurotoxicity in neuronal cells.

• AMPK-mediated autophagy by naringenin mediates its neuroprotection.

• This study not only establishes the underlying mechanism but also provides the basis for finding the strategy in treating the Aβ pathology.

Electronic Supplementary Material

Supplementary Fig. 1

(a) Screening of various compounds for AMPK induction with metformin (Met) as the standard. (b) Cell viability assay of naringenin at different concentrations in differentiated N2a cells and primary mouse neurons. (c) In-silco evaluation for molecular docking of naringenin with AMPK compared to AICAR. (d) Induction of autophagy by naringenin at different concentrations in N2a cells(PNG 851 kb)

High resolution (TIF 3678 kb)

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Ahsan, A.U., Sharma, V.L., Wani, A. et al. Naringenin Upregulates AMPK-Mediated Autophagy to Rescue Neuronal Cells From β-Amyloid (1–42) Evoked Neurotoxicity. Mol Neurobiol 57, 3589–3602 (2020).

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