Vitamin D-binding protein-loaded PLGA nanoparticles suppress Alzheimer's disease-related pathology in 5XFAD mice

Jeon, Seong Gak; Cha, Moon-Yong; Kim, Jin-il; Hwang, Tae-Yeon; Kim, Kyoung Ah; Kim, Tae Hyoung; Song, Ki Chang; Kim, Jwa-Jin; Moon, Minho

doi:10.1016/j.nano.2019.02.004

Cited by 84 publications

(49 citation statements)

References 64 publications

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“…5XFAD mice overexpress human amyloid precursor protein (APP) and presenilin-1 (PS1) mutants, namely the Swedish (K670 N, M671 L), Florida (I716V), and London (V717I) mutations in APP and the PS1 mutations M146 L and L286 V. Male 5XFAD mice and female B6/SJL were obtained from the Jackson Laboratory (Bar Harbor, ME, USA) and maintained in the Korea Institute of Oriental Medicine (KIOM). The offspring were genotyped by polymerase chain reaction analysis using tail DNA to identify mice with transgenic genes [14, 15]. Four animals per cage were housed in an environment with a temperature of 21 ± 3 °C and humidity of 50 ± 10% with a 12-h light/dark cycle (light on 07:00–19:00 h).…”

Section: Methodsmentioning

confidence: 99%

Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer’s disease animal model

Cai

Lee

Yang

2019

J Neuroinflammation

107

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BackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive abilities and memory leading to dementia. Electroacupuncture (EA) is a complementary alternative medicine approach, applying an electrical current to acupuncture points. In clinical and animal studies, EA causes cognitive improvements in AD and vascular dementia. However, EA-induced changes in cognition and microglia-mediated amyloid β (Aβ) degradation have not been determined yet in AD animals. Therefore, this study investigated the EA-induced molecular mechanisms causing cognitive improvement and anti-inflammatory activity in five familial mutation (5XFAD) mice, an animal model of AD.Methods5XFAD mice were bilaterally treated with EA at the Taegye (KI3) acupoints three times per week for 2 weeks. To evaluate the effects of EA treatment on cognitive functions, novel object recognition and Y-maze tests were performed with non-Tg, 5XFAD (Tg), and EA-treated 5XFAD (Tg + KI3) mice. To examine the molecular mechanisms underlying EA effects, western blots, immunohistochemistry, and micro-positron emission tomography scans were performed. Furthermore, we studied synapse ultrastructures with transmission electron microscopy and used electrophysiology to investigate EA effects on synaptic plasticity in 5XFAD mice.ResultsEA treatment significantly improved working memory and synaptic plasticity, alleviated neuroinflammation, and reduced ultrastructural degradation of synapses via upregulation of synaptophysin and postsynaptic density-95 protein in 5XFAD mice. Furthermore, microglia-mediated Aβ deposition was reduced after EA treatment and coincided with a reduction in amyloid precursor protein.ConclusionsOur findings demonstrate that EA treatment ameliorates cognitive impairment via inhibition of synaptic degeneration and neuroinflammation in a mouse model of AD.

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Section: Methodsmentioning

confidence: 99%

Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer’s disease animal model

Cai

Lee

Yang

2019

J Neuroinflammation

107

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“…In fact, PLGA can attenuate death of cultured neurons caused by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (that is MPTP, used in the development of an animal model of Parkinson Disease) by repairing impaired lysosomal function [43]. Additionally, it has been reported that PLGA nanoparticles conjugated with various drugs/agents can have beneficial effects on cellular and/or animal models of AD [44][45][46][47][48][49][50][51][52]. However, it remains unclear if native PLGA itself (that is unconjugated with any drugs/molecules) has an intrinsic activity to protect cultured neurons against Ab-mediated toxicity by restoring lysosomal integrity [43].…”

Section: Introductionmentioning

confidence: 99%

Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β‐amyloid‐toxicity

Wang

Anand

et al. 2020

Neuropathology Appl Neurobio

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Background Evidence suggests that amyloid β (Aβ) peptides play an important role in the degeneration of neurons during the development of Alzheimer's disease (AD), the prevalent cause of dementia affecting the elderly. The endosomal–lysosomal system, which acts as a major site for Aβ metabolism, has been shown to exhibit abnormalities in vulnerable neurons of the AD brain, reflected by enhanced levels/expression of lysosomal enzymes including cathepsin D (CatD). At present, the implication of CatD in selective neuronal vulnerability in AD pathology remains unclear. Methods We evaluated the role of CatD in the degeneration of neurons in Aβ‐treated cultures, transgenic AD mouse model (that is 5xFAD) and post mortem AD brain samples. Results Our results showed that Aβ1‐42‐induced toxicity in cortical cultured neurons is associated with impaired lysosomal integrity, enhanced levels of carbonylated proteins and tau phosphorylation. The cellular and cytosolic levels/activity of CatD are also elevated in cultured neurons following exposure to Aβ peptide. Additionally, we observed that CatD cellular and subcellular levels/activity are increased in the affected cortex, but not in the unaffected cerebellum, of 5xFAD mice and post mortem AD brains. Interestingly, treatment of cultured neurons with nanoparticles PLGA, which targets lysosomal system, attenuated Aβ toxicity by reducing the levels of carbonylated proteins, tau phosphorylation and the level/distribution/activity of CatD. Conclusion Our study reveals that increased cytosolic level/activity of CatD play an important role in determining neuronal vulnerability in AD. Additionally, native PLGA can protect neurons against Aβ toxicity by restoring lysosomal membrane integrity, thus signifying its implication in attenuating AD.

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“…This resulted in an improvement of cognitive function and reduced levels of Aβ 42 in the hippocampus along with decreased tau phosphorylation in the parietal cortex of a mouse model with AD-related memory impairment [60]. In line, a novel study from 2019 reported an improvement of the AD-related pathology in 5xFAD mice after intravenous injection of vitamin D-binding protein which was loaded on a biocompatible polymer (PLGA) [61]. Especially cell culture and animal-based studies are indispensable for clarifying the molecular mechanisms of vitamin D action in neurodegenerative diseases.…”

Section: Alzheimer's Diseasementioning

confidence: 93%

The Effects of Vitamin D Deficiency on Neurodegenerative Diseases

Lauer¹,

Janitschke²,

Hartmann³

et al. 2020

Vitamin D Deficiency

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Approximately 90% of the elderly population in the western countries has at least a mild to moderate vitamin D hypovitaminosis. Besides the well-known function of vitamin D in calcium homeostasis, it has been recently found that several enzymes and receptors involved in its homeostasis are expressed in the nervous system and brain suggesting also an important role in the brain homeostasis. Interestingly, epidemiological and clinical studies found reduced vitamin D level associated with an increased risk of several neurodegenerative disorders. In this chapter, we focus on a potential link between vitamin D and Alzheimer's disease, Parkinson's disease, multiple sclerosis, prion disease, and motor neuron disease. Epidemiological studies were summarized, an overview of the known potential underlying pathomolecular mechanisms are given, and results from clinical studies dealing with vitamin D supplementation were presented. As an outlook, recent literature suggesting an impact of vitamin D on autism spectrum disease, depression, and schizophrenia are briefly discussed. In conclusion, the identification of an abundant vitamin D metabolism in the brain and the tight link between the increasing number of several neurological and mental disorders emphasize the need of further research making a clear recommendation of the intake and supplementation of vitamin D in a growing elderly population.

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Vitamin D-binding protein-loaded PLGA nanoparticles suppress Alzheimer's disease-related pathology in 5XFAD mice

Cited by 84 publications

References 64 publications

Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer’s disease animal model

Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer’s disease animal model

Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β‐amyloid‐toxicity

The Effects of Vitamin D Deficiency on Neurodegenerative Diseases

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