Protection against Neurodegeneration in the Hippocampus Using Sialic Acid- and 5-HT-Moduline-Conjugated Lipopolymer Nanoparticles

Abstract

Significant involvement of oxidative stress in the brain can develop Alzheimer’s disease (AD); however, a great number of clinical trials explains the limited success of antioxidant therapy in dealing with this neurodegenerative disease. Here, we established a lipopolymer system of poly­(lactide-co-glycolide) (PLGA) nanoparticles (NPs) incorporated with phosphatidic acid (PA) and modified with sialic acid (SA) and 5-hydroxytryptamine-moduline (5HTM) to improve quercetin (QU) activity against oxidative stress induced by amyloid-β (Aβ) deposits. Morphological studies revealed a uniform exterior of QU-SA-5HTM-PA-PLGA NPs with a spherical structure and enhanced aggregation with inclusion of PA in the formulation. A better brain-targeted delivery of the lipopolymeric NPs was verified from the high blood–brain barrier (BBB) permeability of QU through strong interactions of surface SA and 5HTM with O-linked N-acetylglucosamine and 5-HT1B receptors, respectively. Immunofluorescence staining images also supported QU-SA-5HTM-PA-PLGA NPs to traverse the microvessels of AD rat brain. Western blot analysis showed that QU-loaded PA-PLGA NPs suppressed caspase-3 expression. The ability of the nanocarriers to recognize Aβ fibrils was demonstrated from the reduced senile plaque formation and the attenuated acetylcholinesterase and malondialdehyde activity in the hippocampus. Hence, the medication of QU-SA-5HTM-PA-PLGA NPs can facilitate the BBB penetration and prevent Aβ accumulation, lipid peroxidation, and neuronal apoptosis for the AD management.

Nanoparticle Brain Delivery: A Guide to Verification Methods

“…Using fluorescence microscopy, Mulik et al saw fluorescent-labeled NPs within brain cells [46].Åslund et al used CLSM to image fluorescent dye-containing NPs, and tomato lectin-labeled blood vessels, and saw NP fluorescent dye outside of the brain microvasculature [47]. Some details of these studies and those reported by others who used CLSM are below and/or in Table 4 [22,24,25,[47][48][49][50][51][52][53][54][55].…”

Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State

“…Microglia contain surface sialic acid and this moiety is tightly regulated. It has been shown that sialic acid can attenuate the extent of inflammatory damage inflicted by microglia involvement (Griciuc et al, 2013 ; Miles et al, 2019 ; Yang et al, 2019 ; Puigdellivol et al, 2020 ). If sialic acid is abundant, microglia are not activated toward phagocytosis.…”

A stimuli-responsive polymer modified nanopore for measuring β-amyloid peptide and zinc ions in brains of live mice with Alzheimer's disease

“…Here, a four-component copolymer was integrated into the inner surface of a glass nanopore (Scheme 1). Inspired by a role of sialic acid (SA) on cell membranes in living systems-specifically the presentation of SA as clusters on cell membranes being able to promote the deposition of Aβ with multivalent interactions [20][21][22] -SA in our current work was covalently grafted onto the polymer chains of the four-component copolymer for highly sensitive detection of Aβ monomers. The polymers provided abundant recognition sites, which promoted the binding of targets.…”