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Biophysical, Biochemical, and Behavioral Implications of ApoE3 Conjugated Donepezil Nanomedicine in a Aβ1–42 Induced Alzheimer’s Disease Rat Model

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Neurosci. 2020, 11, 24, 4139-4151
    Research Article

    Biophysical, Biochemical, and Behavioral Implications of ApoE3 Conjugated Donepezil Nanomedicine in a Aβ1–42 Induced Alzheimer’s Disease Rat Model
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    • Kowthavarapu Venkata Krishna
      Kowthavarapu Venkata Krishna
      Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, 345055 Pilani, Rajasthan, India
      More by Kowthavarapu Venkata Krishna
    • Ranendra Narayan Saha
      Ranendra Narayan Saha
      Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, 345055 Pilani, Rajasthan, India
      Department of Biotechnology, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Dubai Campus, Dubai International Academic City, P.O. Box 345055, Dubai, United Arab Emirates
      More by Ranendra Narayan Saha
    • Sunil Kumar Dubey*
      Sunil Kumar Dubey
      Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, 345055 Pilani, Rajasthan, India
      *Phone: +91 8239703734. Email: [email protected]
      More by Sunil Kumar Dubey
      Orcidhttp://orcid.org/0000-0002-7554-3232
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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2020, 11, 24, 4139–4151
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    https://doi.org/10.1021/acschemneuro.0c00430
    Published November 28, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Alzheimer’s disease (AD) is a progressive neurological disorder and is the most common type of dementia. Amyloid β (Aβ) plaques play an important role in the pathophysiology of AD. However, the existing therapeutic strategies are not effective for the management of both Aβ-induced neurotoxicity and Aβ fibrils clearance in biological conditions. Herein, we have developed lipoprotein conjugated polymeric nanoparticles that can boost the clearance rate of Aβ fibrils and mitigate Aβ-induced neurotoxicity in AD rat. These nanoparticles were designed by loading donepezil in an amphiphilic polymer with a lipoprotein (ApoE3) integrated over the surface. Polymeric nanoparticles were prepared by a nanoprecipitation method, and ApoE3 was conjugated to the polymer layer by polysorbate 80. In the present study, we intended to examine the protective effect of ApoE3 nanoparticles against Aβ-induced neurotoxicity both in vitro and in vivo to evaluate if these can reduce the Aβ fibril formation and cognitive and behavioral deficits observed in AD induced rats. In the in vitro study, neurotoxicity induced by Aβ1–42 in human neuroblastoma (SH-SY5Y) cells was found to be significantly reduced upon treatment with ApoE3 donepezil nanoparticles. The presence of the ApoE3 significantly modified the morphology of Aβ fibrils and also inhibited the formation Aβ oligomers. Moreover, in the in vivo study, following treatment, AD induced rats were tested on Morris water maze (MWM) and passive avoidance task for their cognitive ability and sacrificed for biochemical estimations. From our observations, ApoE3 donepezil nanoparticles exhibited neuroprotection in the Aβ1–42 induced model by mitigating the pathological features and cognitive impairments. Thus, we anticipate that the nanosized lipoprotein carriers will possibly offer a rational therapeutic strategy in the formulation development of AD.

    Copyright © 2020 American Chemical Society

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    • Standardization of ICV administration and treatment schedule; thermal analysis; Aβ1–42 aggregation rate kinetics sigmoidal curve fitting (PDF)

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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2020, 11, 24, 4139–4151
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschemneuro.0c00430
    Published November 28, 2020
    Copyright © 2020 American Chemical Society
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