Significance of native PLGA nanoparticles in the treatment of Alzheimer's disease pathology

Anand, Bibin G.; Wu, Qi; Nakhaei‐Nejad, Maryam; Karthivashan, Govindarajan; Dorosh, Lyudmyla; Amidian, Sara; Dahal, Abhishek; Li, Xiuju; Stepanova, Maria; Wille, Holger; Giuliani, Fabrizio; Kar, Satyabrata

doi:10.1016/j.bioactmat.2022.05.030

Cited by 16 publications

(18 citation statements)

References 82 publications

(135 reference statements)

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“…Thus, molecules that target different facets of both Aβ and tau pathology may offer a better prospect to treat AD than those targeting either protein independently. Recently we have reported that native PLGA can inhibit not only spontaneous aggregation of Aβ but also can trigger dismantling of Aβ aggregates in a dose-dependent manner 28 , 29 . The present results using ThT kinetic assay showed that Aβ seed-induced tau aggregation with or without heparin is inhibited by native PLGA.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the evidence that native PLGA can suppress tau aggregation in the absence of Aβ seed, it could not be excluded that PLGA by interacting directly with the aggregate-prone hexapeptide motifs on MTBDs can hinder tau dimerization and/or its assembly. Furthermore, as native PLGA nanoparticles are able to suppress tau fibrilization irrespective of Aβ seed and also can attenuate Aβ aggregation by interacting with its hydrophobic domain Lys 16 to Ala 21 28 , it is of interest to determine if PLGA prevents tau aggregation by intervening with the common interface regulating tau and Aβ binding. Our results further revealed that native PLGA inhibits aggregation of both 4R tau as well as 3R tau – which exhibit different aggregation kinetics but are found together in the NFTs 32 .…”

Section: Discussionmentioning

confidence: 99%

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Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer’s disease pathology

Paul,

Patel,

Cho

et al. 2024

Sci Rep

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Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer’s disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aβ and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aβ aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aβ seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aβ1-42 seeds enhanced aggregation of tau protein in the presence and absence of heparin and the effect was attenuated by native PLGA nanoparticles. Interestingly, PLGA inhibited aggregation of both 4R and 3R tau isoforms involved in the formation of neurofibrillary tangles in AD brains. Furthermore, Aβ seed-induced tau aggregation in the presence of arachidonic acid was suppressed by native PLGA. Collectively, our results suggest that native PLGA nanoparticles can inhibit the Aβ seed-induced aggregation of different tau protein isoforms highlighting their therapeutic implication in the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer’s disease pathology

Paul,

Patel,

Cho

et al. 2024

Sci Rep

Self Cite

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“…Recently, PLGA NPs have been studied and shown remarkable potential for various CNS diseases, such as ischemic stroke [ 41 ], Alzheimer’s disease [ 42 ], glioma [ 43 , 44 ], Parkinson’s disease [ 45 , 46 ], etc. Though a lot of research efforts have been involved in the application of PLGA NPs in drug delivery to CNS, there are limited studies on the application of PLGA NPs in HAND.…”

Section: Discussionmentioning

confidence: 99%

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice

Zhou,

Godse,

Sinha

et al. 2024

Pharmaceutics

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Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.

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“…The NPs are stimuli-responsive; they respond to mildly acidic environments (~ pH 6.0 for PLGA NPs and AcNPs) or ultraviolet (UV) light (~ 365 nm for PaNPs) [ 30 , 32 , 86 – 89 ]. Notably, PLGA NPs and AcNPs have demonstrated restoration of lysosomal acidification and autophagic function as well as rescue of neurodegenerative pathology in several cellular and mouse models of AD and PD [ 11 , 13 , 30 , 32 , 87 , 90 ], and in a Drosophila model of ALS (Fig. 4 a, b) [ 91 ].…”

Section: Restoring Lysosomal Acidification As a Therapeutic Interventionmentioning

confidence: 99%

Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

2023

Transl Neurodegener

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Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases.

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Significance of native PLGA nanoparticles in the treatment of Alzheimer's disease pathology

Cited by 16 publications

References 82 publications

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer’s disease pathology

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer’s disease pathology

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice

Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

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