Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via canonical Wnt/β-catenin pathway.
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.
CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
Shashi Kant
SK
Tiwari
Swati
S
Agarwal
Brashket
B
Seth
Anuradha
A
Yadav
Saumya
S
Nair
Priyanka
P
Bhatnagar
Madhumita
M
Karmakar
Manisha
M
Kumari
Lalit Kumar Singh
LK
Chauhan
Devendra Kumar
DK
Patel
Vikas
V
Srivastava
Dhirendra
D
Singh
Shailendra Kumar
SK
Gupta
Anurag
A
Tripathi
Rajnish Kumar
RK
Chaturvedi
Kailash Chand
KC
Gupta
D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy*; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D051381:Rats; D000091042:Reelin Protein; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D000091042:Reelin Protein; C000717129:Reln protein, rat; D051153:Wnt Proteins; D051176:beta Catenin; D003474:Curcumin