Biophysical, Biochemical, and Behavioral Implications of ApoE3 Conjugated Donepezil Nanomedicine in a Aβ<sub>1–42</sub> Induced Alzheimer’s Disease Rat Model
Kowthavarapu Venkata Krishna, Ranendra Narayan Saha, Sunil Kumar Dubey
Abstract
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.