Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

Author(s): Zhi-You Cai*, Chuan-Ling Wang, Tao-Tao Lu, Wen-Ming Yang.

Journal Name: Current Molecular Medicine

Volume 19 , Issue 5 , 2019

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Abstract:

Background: Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.

Methods: The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.

Results: BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.

Conclusion: BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

Keywords: Berberine, amyloid-β, liver kinase B1, 5'-adenosine monophosphate-activated protein kinase, pathogenesis, LKB1/AMPK signaling.

[1]
Cornutiu G. The Epidemiological Scale of Alzheimer’s Disease. J Clin Med Res 2015; 7(9): 657-66.
[2]
Heyman A, Wilkinson WE, Stafford JA, Helms MJ, Sigmon AH, Weinberg T. Alzheimer’s disease: a study of epidemiological aspects. Ann Neurol 1984; 15(4): 335-41.
[3]
Windisch M. We can treat Alzheimer’s disease successfully in mice but not in men: failure in translation? A perspective. Neurodegener Dis 2014; 13(2-3): 147-50.
[4]
El Haj M, Gallouj K, Dehon H, Roche J, Laroi F. Hallucinations in Alzheimer’s disease: failure to suppress irrelevant memories. Cogn Neuropsychiatry 2018; 23(3): 142-53.
[5]
Sanchez SM, Abulafia C, Duarte-Abritta B, et al. Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer’s Disease. J Alzheimers Dis 2017; 60(3): 1183-93.
[6]
Cai Z, Wang C, Yang W. Role of berberine in Alzheimer’s disease. Neuropsychiatr Dis Treat 2016; 12: 2509-20.
[7]
Hussien HM, Abd-Elmegied A, Ghareeb DA, Hafez HS, Ahmed HEA, El-Moneam NA. Neuroprotective effect of berberine against environmental heavy metals-induced neurotoxicity and Alzheimer’s-like disease in rats. Food Chem Toxicol 2018; 111: 432-44.
[8]
Cai Z, Wang C, He W, Chen Y. Berberine alleviates amyloid-beta pathology in the brain of APP/PS1 transgenic mice via inhibiting beta/gamma-secretases activity and enhancing alpha-secretases. Curr Alzheimer Res 2018; 15(11): 1045-52.
[9]
He W, Wang C, Chen Y, He Y, Cai Z. Berberine attenuates cognitive impairment and ameliorates tau hyperphos-phorylation by limiting the self-perpetuating pathogenic cycle between NF-kappaB signaling, oxidative stress and neuroinflammation. Pharmacol Rep 2017; 69(6): 1341-8.
[10]
Koppel J, Jimenez H, Adrien L, et al. Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer’s disease. Alzheimers Dement (N Y) 2016; 2(2): 121-30.
[11]
Du LL, Chai DM, Zhao LN, et al. AMPK activation ameliorates Alzheimer’s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer’s disease model in rats. J Alzheimers Dis 2015; 43(3): 775-84.
[12]
Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010; 468(7324): 653-8.
[13]
Jansen M, Ten Klooster JP, Offerhaus GJ, Clevers H. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol Rev 2009; 89(3): 777-98.
[14]
Sung MM, Zordoky BN, Bujak AL, et al. AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc Res 2015; 107(2): 235-45.
[15]
Perera ND, Turner BJ. AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis. Neurochem Res 2016; 41(3): 544-53.
[16]
Pelosse M, Cottet-Rousselle C, Grichine A, Berger I, Schlattner U. Genetically Encoded Fluorescent Biosensors to Explore AMPK Signaling and Energy Metabolism. EXS 2016; 107: 491-23.
[17]
Mitsuhashi K, Senmaru T, Fukuda T, et al. Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. Endocrine 2016; 51(1): 174-84.
[18]
Green AS, Chapuis N, Lacombe C, Mayeux P, Bouscary D, Tamburini J. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle 2011; 10(13): 2115-20.
[19]
Park SY, Lee HR, Lee WS, et al. Cilostazol Modulates Autophagic Degradation of beta-Amyloid Peptide via SIRT1-Coupled LKB1/AMPKalpha Signaling in Neuronal Cells. PLoS One 2016; 11(8): e0160620.
[20]
Cai Z, Yan LJ, Li K, Quazi SH, Zhao B. Roles of AMP-activated protein kinase in Alzheimer’s disease. Neuromolecular Med 2012; 14(1): 1-14.
[21]
Shen Y, Ye B, Chen P, et al. Cognitive Decline, Dementia, Alzheimer’s Disease and Presbycusis: Examination of the Possible Molecular Mechanism. Front Neurosci 2018; 12: 394.
[22]
Son SM, Kang S, Choi H, Mook-Jung I. Statins induce insulin-degrading enzyme secretion from astrocytes via an autophagy-based unconventional secretory pathway. Mol Neurodegener 2015; 10: 56.
[23]
Sarantseva SV, Bol’shakova OI, Timoshenko SI, Rodin DI, Vitek MP, Shvartsman AL. [Studying pathogenesis of Alzheimer's disease in a Drosophila melanogaster model: human APP overexpression in the brain of transgenic flies leads to deficit of the synaptic protein synaptotagmin]. Genetika 2009; 45(1): 119-26.
[24]
Josselyn SA, Shi C, Carlezon WA Jr, Neve RL, Nestler EJ, Davis M. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J Neurosci 2001; 21(7): 2404-12.
[25]
Brightwell JJ, Smith CA, Neve RL, Colombo PJ. Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem 2007; 14(3): 195-9.
[26]
Yao Y, Chinnici C, Tang H, Trojanowski JQ, Lee VM, Pratico D. Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis. J Neuroinflammation 2004; 1(1): 21.
[27]
Candore G, Bulati M, Caruso C, et al. Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res 2010; 13(2-3): 301-13.
[28]
Durairajan SS, Liu LF, Lu JH, et al. Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol Aging 2012; 33(12): 2903-19.


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Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [342 - 348]
Pages: 7
DOI: 10.2174/1566524019666190315164120
Price: $65

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