Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via canonical Wnt/β-catenin pathway

Shashi Kant Tiwari, Swati Agarwal, Brashket Seth, Anuradha Yadav, Saumya Nair, Priyanka Bhatnagar, Madhumita Karmakar, Manisha Kumari, Lalit Kumar Singh Chauhan, Devendra Kumar Patel, Vikas Srivastava, Dhirendra Singh, Shailendra Kumar Gupta, Anurag Tripathi, Rajnish Kumar Chaturvedi, Kailash Chand Gupta

Research output: Contribution to journalArticlepeer-review

Abstract

Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism.

Original languageEnglish (US)
Pages (from-to)76-103
Number of pages28
JournalACS Nano
Volume8
Issue number1
DOIs
StatePublished - Jan 28 2014
Externally publishedYes

Keywords

  • Alzheimer's disease
  • curcumin
  • nanoparticles
  • neural stem cells
  • neurodegenerative disorders
  • neuronal differentiation
  • regenerative medicine

ASJC Scopus subject areas

  • General Materials Science
  • General Engineering
  • General Physics and Astronomy

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