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.

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 ß42 (Aß42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3ß/GSK3ß, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aß42 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 Aß42, 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.

Neuroprotective effect of berberine against environmental heavy metals-induced neurotoxicity and Alzheimer's-like disease in rats.

Heavy metals are reported as neurodegenerative disorders progenitor. They play a role in the precipitation of abnormal ß-amyloid protein and hyper-phosphorylated tau, the main hallmarks of Alzheimer's disease (AD). The present study aimed to validate the heavy metals-induced Alzheimer's-like disease in rats as an experimental model of AD and explore the therapeutic effect of berberine via tracking its effect on the oxidative stress-inflammatory pathway. Alzheimer's-like disease was induced in rats orally by a mixture of aluminium, cadmium and fluoride for three months, followed by berberine treatment for another one month. Berberine significantly improved the cognitive behaviors in Morris water maze test and offered a protective effect against heavy metals-induced memory impairment. Docking results showed that berberine inhibited AChE, COX-2 and TACE. Matching with in silico study, berberine downregulated the AChE expression and inhibited its activity in the brain tissues. Also, it normalized the production of TNF- α, IL-12, IL-6 and IL-1ß. Moreover, it evoked the production of antioxidant Aß40 and inhibited the formation of Aß42, responsible for the aggregations of amyloid-ß plaques. Histopathological examination confirmed the neuroprotective effect of berberine. The present data advocate the possible beneficial effect of berberine as therapeutic modality for Alzheimer's disease via its antiinflammatory/antioxidant mechanism.