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Berberine and Alzheimer Dementia

Berberine Alleviates Amyloid β-Induced Mitochondrial Dysfunction and Synaptic Loss

Synaptic structural and functional damage is a typical pathological feature of Alzheimer’s disease (AD). Normal axonal mitochondrial function and transportation are vital to synaptic function and plasticity because they are necessary for maintaining cellular energy supply and regulating calcium and redox signalling as well as synaptic transmission and vesicle release. Amyloid-β (Aβ) accumulation is another pathological hallmark of AD that mediates synaptic loss and dysfunction by targeting mitochondria.

Therefore, it is important to develop strategies to protect against synaptic mitochondrial damage induced by Aβ. The present study examined the beneficial effects of berberine, a natural isoquinoline alkaloid extracted from the traditional medicinal plant Coptis chinensis, on Aβ-induced mitochondrial and synaptic damage in primary cultured hippocampal neurons.  Berberine alleviates axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in hippocampal neurons. Although the underlying protective mechanism remains to be elucidated, the data suggest that the effects of berberine were in part related to its potent antioxidant activity.

These findings highlight the neuroprotective and specifically mitoprotective effects of berberine treatment under conditions of Aβ enrichment.

Synaptic dysfunction is an early event in the pathogenesis of Alzheimer’s disease (AD), and memory and cognitive loss is more strongly correlated with synaptic dysfunction than with the development of senile plaques, neurofibrillary tangles, or gliosis [1–3]. Synapses are the basic functional unit of signal transduction in the central nervous system, forming connections and transmitting electrical and chemical signals between neurons.

Accordingly, synapses are sites of high energy demand [4]. Adequate mitochondrial function is critical to meeting the high energy requirements of the synapse. Synaptic mitochondria are synthesized in neuronal soma, transported to axons and dendrites, and distributed among synapses to support synaptic function and modulate calcium homeostasis [5, 6]. Recent studies also indicate that the appropriate intracellular distribution and trafficking of mitochondria are essential for normal neuronal functions including neurotransmission, synaptic plasticity, and axonal outgrowth [7–9]. Importantly, abnormalities in mitochondrial function play an important role in AD [6].

Amyloid β (Aβ) is an important pathogenic peptide that is associated with AD and directly disturbs mitochondrial function [10, 11]. Aβ is transported into the mitochondria via the receptor for advanced glycation end products, the translocase of the outer mitochondrial membrane, or endoplasmic reticulum-mitochondrial crosstalk [10, 12–14]. Mitochondrial Aβ accumulation impairs mitochondrial respiration, decreases ATP production and the mitochondrial membrane potential, and increases calcium influx, cytochrome c release, and oxidative stress [15, 16]. Furthermore, the interaction of Aβ with proteins such as alcohol dehydrogenase and cyclophilin D exacerbates Aβ-induced mitochondrial and neuronal stress [17–20].

Recent studies indicate that brief exposure of cultured hippocampal neurons to relatively low concentrations of Aβ is sufficient to mediate the rapid (within 10 min) and severe impairment of mitochondrial transport in the absence of apparent cell death or significant morphological changes [21]. Taken together, these studies suggest that mitochondria are a direct site for Aβ-mediated cellular perturbation and that overt mitochondrial dysfunction occurs in an Aβ-rich environment.

Berberine is a natural isoquinoline alkaloid derived from the traditional medicinal plant Coptis chinensis

that has numerous pharmacological properties including antimicrobial, antioxidant, anti-inflammatory, antidiarrheal, antidiabetic, antidyslipidemic, and antitumour activities [22, 23]. Recent studies have indicated that berberine treatment significantly improves memory and cognitive dysfunction in different animal models of AD [24, 25].

Due to its ability to cross the blood-brain barrier [26], berberine exerts beneficial neuroprotective effects against homocysteic acid, calyculin A, 6-hydroxydopamine, streptozotocin, and mercury-induced neurodegeneration as demonstrated through in vivo and in vitro studies [27–31]. Furthermore, berberine treatment inhibits Aβ25–35-induced cytotoxicity and apoptosis by suppressing the release of cytochrome C, apoptotic protein expression, and caspase activity in primary cultured hippocampal neurons [32]. Yet whether berberine has protective effects against Aβ-induced mitochondrial dysfunction and synaptic loss in neurons remains unclear. Therefore, we investigated the effects of berberine on Aβ oligomer-induced axonal mitochondrial dysfunction using an in vitro hippocampal neuron-cultured mode.

Reference article :

AbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsAbbreviationsData AvailabilityConflicts of InterestAcknowledgmentsReferencesCopyright
Research Article | Open Access
Volume 2019 |Article ID 7593608 | 11 pages | https://doi.org/10.1155/2019/7593608
Berberine Alleviates Amyloid β-Induced Mitochondrial Dysfunction and Synaptic Loss
Chunhui Zhao,1,2,3 Ping Su,1,2,3 Cui Lv,1,2,4 Limin Guo,1,2,5 Guoqiong Cao,1,2,5 Chunxia Qin,1,2,5 and Wensheng Zhang1,2,5,6
Academic Editor: Ana Lloret

References

  1. S. Hauptmann, I. Scherping, S. Dröse et al., “Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice,” Neurobiology of Aging, vol. 30, no. 10, pp. 1574–1586, 2009.View at: Publisher Site | Google Scholar

  2. J. Pozueta, R. Lefort, and M. L. Shelanski, “Synaptic changes in Alzheimer’s disease and its models,” Neuroscience, vol. 251, no. 5, pp. 51–65, 2013.View at: Publisher Site | Google Scholar

  3.  P. H. Reddy, R. Tripathi, Q. Troung et al., “Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: implications to mitochondria-targeted antioxidant therapeutics,” Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, vol. 1822, no. 5, pp. 639–649, 2012.View at: Publisher Site | Google Scholar

  4. T. J. Ryan and S. G. Grant, “The origin and evolution of synapses,” Nature Reviews Neuroscience, vol. 10, no. 10, pp. 701–712, 2009.View at: Publisher Site | Google Scholar

  5.  R. J. Evans, V. Derkach, and A. Surprenant, “ATP mediates fast synaptic transmission in mammalian neurons,” Nature, vol. 357, no. 6378, pp. 503–505, 1992.View at: Publisher Site | Google Scholar

  6. H. Du, L. Guo, S. Yan, A. A. Sosunov, G. M. McKhann, and S. S. Yan, “Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 43, pp. 18670–18675, 2010.View at: Publisher Site | Google Scholar

  7. Z. Li, K. I. Okamoto, Y. Hayashi, and M. Sheng, “The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses,” Cell, vol. 119, no. 6, pp. 873–887, 2004.View at: Publisher Site | Google Scholar

  8. D. T. Chang, A. S. Honick, and I. J. Reynolds, “Mitochondrial trafficking to synapses in cultured primary cortical neurons,” The Journal of Neuroscience, vol. 26, no. 26, pp. 7035–7045, 2006.View at: Publisher Site | Google Scholar

  9. Q. Cai and P. Tammineni, “Alterations in mitochondrial quality control in Alzheimer’s disease,” Frontiers in Cellular Neuroscience, vol. 10, no. 1, p. 24, 2016.View at: Publisher Site | Google Scholar

  10. P. H. Reddy, “Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease,” Experimental Neurology, vol. 218, no. 2, pp. 286–292, 2009.View at: Publisher Site | Google Scholar

  11. P. H. Reddy and M. F. Beal, “Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease,” Trends in Molecular Medicine, vol. 14, no. 2, pp. 45–53, 2008.View at: Publisher Site | Google Scholar

  12. K. Takuma, F. Fang, W. Zhang et al., “RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 20021–20026, 2009.View at: Publisher Site | Google Scholar

  13. C. A. Hansson Petersen, N. Alikhani, H. Behbahani et al., “The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 35, article 13145, 13150 pages, 2008.View at: Publisher Site | Google Scholar

  14. L. Hedskog, C. M. Pinho, R. Filadi et al., “Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 19, pp. 7916–7921, 2013.View at: Publisher Site | Google Scholar

  15. J. X. Chen and S. S. Yan, “Role of mitochondrial amyloid-β in Alzheimer’s disease,” Journal of Alzheimers Disease, vol. 20, no. s2, pp. S569–S578, 2010.View at: Publisher Site | Google Scholar

  16. F. Akhter, D. Chen, S. F. Yan, and S. S. Yan, “Chapter Eleven – Mitochondrial perturbation in Alzheimer’s disease and diabetes,” Progress in Molecular Biology and Translational Science, vol. 146, pp. 341–361, 2017.View at: Publisher Site | Google Scholar

  17.  K. Takuma, J. Yao, J. Huang et al., “ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction,” Faseb Journal, vol. 19, no. 6, pp. 597-598, 2005.View at: Publisher Site | Google Scholar

  18.  J. W. Lustbader, M. Cirilli, C. Lin et al., “ABAD directly links a to mitochondrial toxicity in Alzheimer’s disease,” Science, vol. 304, no. 5669, pp. 448–452, 2004.View at: Publisher Site | Google Scholar

  19.  H. Du, L. Guo, F. Fang et al., “Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease,” Nature Medicine, vol. 14, no. 10, pp. 1097–1105, 2008.View at: Publisher Site | Google Scholar

  20. H. Du, L. Guo, W. Zhang, M. Rydzewska, and S. Yan, “Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model,” Neurobiology of Aging, vol. 32, no. 3, pp. 398–406, 2011.View at: Publisher Site | Google Scholar

  21.  Y. Rui, P. Tiwari, Z. Xie, and J. Q. Zheng, “Acute impairment of mitochondrial trafficking by β-amyloid peptides in hippocampal neurons,” The Journal of Neuroscience, vol. 26, no. 41, pp. 10480–10487, 2006.View at: Publisher Site | Google Scholar

  22.  M. Huang, S. Chen, Y. Liang, and Y. Guo, “The role of berberine in the multi-target treatment of senile dementia,” Current Topics in Medicinal Chemistry, vol. 16, no. 8, pp. 867–873, 2016.View at: Google Scholar

  23. T. Ahmed, A. U. H. Gilani, M. Abdollahi, M. Daglia, S. F. Nabavi, and S. M. Nabavi, “Berberine and neurodegeneration: a review of literature,” Pharmacological Reports, vol. 67, no. 5, pp. 970–979, 2015.View at: Publisher Site | Google Scholar

  24. S. S. Durairajan, L. F. Liu, J. H. Lu et al., “Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model,” Neurobiology of Aging, vol. 33, no. 12, pp. 2903–2919, 2012.View at: Publisher Site | Google Scholar

  25. F. Zhu and C. Qian, “Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer’s disease,” BMC Neuroscience, vol. 7, no. 1, p. 78, 2006.View at: Publisher Site | Google Scholar

  26.  X. Wang, R. Wang, D. Xing et al., “Kinetic difference of berberine between hippocampus and plasma in rat after intravenous administration of Coptidis rhizoma extract,” Life Sciences, vol. 77, no. 24, pp. 3058–3067, 2005.View at: Publisher Site | Google Scholar

  27.  M. Chen, M. Tan, M. Jing et al., “Berberine protects homocysteic acid-induced HT-22 cell death: involvement of Akt pathway,” Metabolic Brain Disease, vol. 30, no. 1, pp. 137–142, 2015.View at: Publisher Site | Google Scholar

  28.  X. Liu, J. Zhou, M. D. Abid et al., “Correction: berberine attenuates axonal transport impairment and axonopathy induced by calyculin a in N2a cells,” PLoS One, vol. 11, no. 3, article e0152609, 2014.View at: Publisher Site | Google Scholar

  29. F. Negahdar, M. Mehdizadeh, M. T. Joghataei, M. Roghani, F. Mehraeen, and E. Poorghayoomi, “Berberine chloride pretreatment exhibits neuroprotective effect against 6-hydroxydopamine-induced neuronal insult in rat,” Iranian Journal of Pharmaceutical Research, vol. 14, no. 4, pp. 1145–1152, 2015.View at: Google Scholar

  30.  A. Kumar, Ekavali, J. Mishra, K. Chopra, and D. K. Dhull, “Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction,” Psychopharmacology, vol. 233, no. 1, pp. 137–152, 2016.View at: Publisher Site | Google Scholar

  31.  A. E. Abdel Moneim, “The neuroprotective effect of berberine in mercury-induced neurotoxicity in rats,” Metabolic Brain Disease, vol. 30, no. 4, pp. 935–942, 2015.View at: Publisher Site | Google Scholar

  32. Y. Liang, M. Huang, X. Jiang, Q. Liu, X. Chang, and Y. Guo, “The neuroprotective effects of berberine against amyloid β-protein-induced apoptosis in primary cultured hippocampal neurons via mitochondria-related caspase pathway,” Neuroscience Letters, vol. 655, pp. 46–53, 2017.View at: Publisher Site | Google Scholar

  33. C. Lv, L. Wang, X. Liu et al., “Geniposide attenuates oligomeric Aβ1-42-induced inflammatory response by targeting RAGE-dependent signaling in BV2 cells,” Current Alzheimer Research, vol. 11, no. 5, pp. 430–440, 2014.View at: Publisher Site | Google Scholar

  34. H. Zhang, C. Zhao, C. Lv et al., “Geniposide alleviates amyloid-induced synaptic injury by protecting axonal mitochondrial trafficking,” Frontiers in Cellular Neuroscience, vol. 10, p. 309, 2017.View at: Publisher Site | Google Scholar

  35. V. Todorova and A. Blokland, “Mitochondria and synaptic plasticity in the mature and aging nervous system,” Current Neuropharmacology, vol. 15, no. 1, pp. 166–173, 2017.View at: Google Scholar

  36. S. M. Cardoso, S. Santos, R. H. Swerdlow, and C. R. Oliveira, “Functional mitochondria are required for amyloid beta-mediated neurotoxicity,” Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology, vol. 15, no. 8, pp. 1439–1441, 2001.View at: Publisher Site | Google Scholar

  37. M. Manczak, T. S. Anekonda, E. Henson, B. S. Park, J. Quinn, and P. H. Reddy, “Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression,” Human Molecular Genetics, vol. 15, no. 9, pp. 1437–1449, 2006.View at: Publisher Site | Google Scholar

  38. L. D. Zorova, V. A. Popkov, E. Y. Plotnikov et al., “Mitochondrial membrane potential,” Analytical Biochemistry, vol. 552, pp. 50–59, 2017.View at: Publisher Site | Google Scholar

  39. V. P. Skulachev, “Mitochondrial filaments and clusters as intracellular power-transmitting cables,” Trends in Biochemical Sciences, vol. 26, no. 1, pp. 23–29, 2001.View at: Publisher Site | Google Scholar

  40. G. A. Banker and W. M. Cowan, “Further observations on hippocampal neurons in dispersed cell culture,” Journal of Comparative Neurology, vol. 187, no. 3, pp. 469–493, 1979.View at: Publisher Site | Google Scholar

  41. Y. L. Siow, L. Sarna, and O. Karmin, “Redox regulation in health and disease — therapeutic potential of berberine,” Food Research International, vol. 44, no. 8, pp. 2409–2417, 2011.View at: Publisher Site | Google Scholar

  42. J.-M. Hwang, C.-J. Wang, F.-P. Chou et al., “Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver,” Archives of Toxicology, vol. 76, no. 11, pp. 664–670, 2002.View at: Publisher Site | Google Scholar

  43. J. Y. Zhou and S. W. Zhou, “Protective effect of berberine on antioxidant enzymes and positive transcription elongation factor b expression in diabetic rat liver,” Fitoterapia, vol. 82, no. 2, pp. 184–189, 2011.View at: Publisher Site | Google Scholar

  44. A. Kumar, K. Ekavali, M. Chopra, R. P. Mukherjee, and D. K. Dhull, “Current knowledge and pharmacological profile of berberine: an update,” European Journal of Pharmacology, vol. 761, pp. 288–297, 2015.View at: Publisher Site | Google Scholar

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