Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer's disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

Samar R Saleh; Aml Abd-Elmegied; Somaya Aly Madhy; Sherine N Khattab; Eman Sheta; Fatma Y Elnozahy; Radwa A Mehanna; Doaa A Ghareeb; Nihad M Abd-Elmonem

doi:10.1016/j.ijpharm.2024.124218

Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer's disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

Int J Pharm. 2024 May 9:658:124218. doi: 10.1016/j.ijpharm.2024.124218. Online ahead of print.

Authors

Samar R Saleh¹, Aml Abd-Elmegied², Somaya Aly Madhy³, Sherine N Khattab⁴, Eman Sheta⁵, Fatma Y Elnozahy⁶, Radwa A Mehanna⁷, Doaa A Ghareeb⁸, Nihad M Abd-Elmonem⁹

Affiliations

¹ Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. Electronic address: samar.saleh@alexu.edu.eg.
² Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
³ Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. Electronic address: Somaya.mady_pg@alexu.edu.eg.
⁴ Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. Electronic address: sherinekhattab@alexu.edu.eg.
⁵ Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Electronic address: iman.sheta@alexmed.edu.eg.
⁶ Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Electronic address: fatma.yousry@alexmed.edu.eg.
⁷ Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, Egypt. Electronic address: radwa.mehanna@alexmed.edu.eg.
⁸ Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. Electronic address: d.ghareeb@alexu.edu.eg.
⁹ Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.

PMID: 38734273
DOI: 10.1016/j.ijpharm.2024.124218

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes severe dementia and memory loss. Surface functionalized poly(lactic-co-glycolic acid) nanoparticles have been reported for better transport through the blood-brain barrier for AD therapy. This study investigated the improved therapeutic potential of berberine-loaded poly(lactic-co-glycolic acid)/Tet-1 peptide nanoparticles (BBR/PLGA-Tet NPs) in a rat model of sporadic AD. BBR was loaded into the PLGA-Tet conjugate. BBR/PLGA-Tet NPs were physicochemically and morphologically characterized. AD was achieved by bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). Cognitively impaired rats were divided into STZ, STZ + BBR, STZ + BBR/PLGA-Tet NPs, and STZ + PLGA-Tet NPs groups. Cognitive improvement was assessed using the Morris Water Maze. Brain acetylcholinesterase and monoamine oxidase activities, amyloid β42 (Aβ42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3β/GSK3β, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aβ42 deposition, Tau hyperphosphorylation, impaired insulin signaling and neuroplasticity, and neuroinflammation. BBR and BBR/PLGA-Tet NPs attenuated STZ-induced hippocampal damage, enhanced cognitive performance, and reduced Aβ42, Tau phosphorylation, and proinflammatory responses. BBR/PLGA-Tet NPs restored neuroplasticity, cholinergic, and monoaminergic function, which are critical for cognition and brain function. BBR/PLGA-Tet NPs may have superior therapeutic potential in alleviating sporadic AD than free BBR due to their bioavailability, absorption, and brain uptake.

Keywords: BBR/PLGA-Tet NPs; Brain targeting; Neuroplasticity; Oxidative stress; pERK/ERK; pGSK3β/GSK3β.