Vitamin D Affects Neuronal Peptides in Neurodegenerative Disease: Differences of V-D2 and V-D3 for Affinity to Amyloid-β and Scrapie Prion Protein In Vitro

Eriodictyol ameliorated cognitive dysfunction in APP/PS1 mice through inhibited ferroptosis via vitamin D receptor mediated Nrf2 activation

10.21203/rs.3.rs-1046295/v1 ◽

2021 ◽

Author(s):

Lin Li ◽

Wenjun Li ◽

Xiangru Zheng ◽

Qinglong Liu ◽

Qian Du ◽

...

Keyword(s):

Vitamin D ◽

Signaling Pathway ◽

Western Blotting ◽

Vitamin D Receptor ◽

Amyloid Β ◽

Qpcr Assay ◽

Aβ Aggregation ◽

The Brain

Abstract Background Alzheimer's disease (AD) is the most common type of neurodegenerative disease in contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound mainly exists in citrus fruits and some Chinese herbal medicine, has been reported with its effect of anti-inflammatory, antioxidant, anti-cancer and neuroprotective effects. However, there are few studies on the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed by behavioral tests. The level of amyloid-β (Aβ) aggregation and hyper-phosphorylation of Tau in the brain of mice were detected by histological analysis and Western blotting. Meanwhile, HT-22 cells which induced by amyloid-β peptide (1-42) (Aβ1−42) oligomer were treated with eriodictyol after which cell viability was determined and the production of p-Tau was tested by Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4(GPX4), were determined both in vivo and in vitro by Fe straining, Western blotting and qPCR assay. Additionally, the expression level of Vitamin D receptor (VDR) and the activity of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested by Western blotting and qPCR assay. After that, the HT-22 cells with VDR knockout were used to explore the potential mechanisms and the relationship between VDR and Nrf2 was further assessed by coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, suppressed Aβ aggregation and the phosphorylated level Tau in the brain of APP/PS1 mice. Meanwhile, eriodictyol could inhibit Tau hyper-phosphorylation and neurotoxicity in HT-22 cells induced by Aβ1−42 oligomer. Furthermore, both in vivo and in vitro, eriodictyol showed the anti-ferroptosis effect and its mechanism may connected with the activation of Nrf2/HO-1 signaling pathway. Additionally, the further experiment explains that the activation of Nrf2/HO-1 signaling pathway with eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes via activating Nrf2/HO-1 signaling pathway mediated by VDR, which provide a new possibility for the treatment of AD.

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Cellular Prion Protein Participates in Amyloid-β Transcytosis across the Blood—Brain Barrier

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.7 ◽

2012 ◽

Vol 32 (4) ◽

pp. 628-632 ◽

Cited By ~ 26

Author(s):

Thorsten Pflanzner ◽

Benjamin Petsch ◽

Bettina André-Dohmen ◽

Andreas Müller-Schiffmann ◽

Sabrina Tschickardt ◽

...

Keyword(s):

Prion Protein ◽

Blood Brain Barrier ◽

Amyloid Β ◽

Cellular Prion Protein ◽

Brain Barrier ◽

Putative Receptor ◽

Blood Brain ◽

In Vitro Bbb Model

The blood—brain barrier (BBB) facilitates amyloid-β (Aβ) exchange between the blood and the brain. Here, we found that the cellular prion protein (PrPc), a putative receptor implicated in mediating Aβ neurotoxicity in Alzheimer's disease (AD), participates in Aβ transcytosis across the BBB. Using an in vitro BBB model, [125I]-Aβ1–40 transcytosis was reduced by genetic knockout of PrPc or after addition of a competing PrPc-specific antibody. Furthermore, we provide evidence that PrPc is expressed in endothelial cells and, that monomeric Aβ1–40 binds to PrPc. These observations provide new mechanistic insights into the role of PrPc in AD.

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Couldα-Synuclein Amyloid-Like Aggregates Trigger a Prionic Neuronal Invasion?

BioMed Research International ◽

10.1155/2015/172018 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Maria Antònia Busquets ◽

Alba Espargaró ◽

Joan Estelrich ◽

Raimon Sabate

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disease ◽

Prion Protein ◽

Intracellular Localization ◽

Lewy Bodies ◽

Key Factors ◽

Neuronal Toxicity

Parkinson’s disease (PD), a progressive neurodegenerative disease primarily affecting voluntary and controlled movement, is characterized by abnormal accumulations ofα-synuclein (α-syn) in intraneuronal Lewy bodies. In the last years, the increased number of evidences from both thein vitroandin vivostudies has shown the ability ofα-syn to misfold in amyloid conformations and to spread via neuron-to-neuron transmission, suggesting a prion-like behaviour. However, in contrast to prion protein (PrP),α-syn transmission is far from neuronal invasion. The high neuronal toxicity of both mature fibres and oligomeric species, as well as the intracellular localization of the protein and the difficulty to be secreted, could be key factors impeding the prion ability ofα-syn aggregates.

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The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Aggregates

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab039 ◽

2021 ◽

Author(s):

Benjamin C Creekmore ◽

Yi-Wei Chang ◽

Edward B Lee

Keyword(s):

Neurodegenerative Disease ◽

Human Tissue ◽

Ex Vivo ◽

Amyloid Β ◽

Atomic Resolution ◽

Resonance Spectroscopy ◽

Aggregate Structure ◽

Ultrastructural Studies ◽

Aggregate Structures

Abstract Neurogenerative diseases are characterized by diverse protein aggregates with a variety of microscopic morphologic features. Although ultrastructural studies of human neurodegenerative disease tissues have been conducted since the 1960s, only recently have near-atomic resolution structures of neurodegenerative disease aggregates been described. Solid-state nuclear magnetic resonance spectroscopy and X-ray crystallography have provided near-atomic resolution information about in vitro aggregates but pose logistical challenges to resolving the structure of aggregates derived from human tissues. Recent advances in cryo-electron microscopy (cryo-EM) have provided the means for near-atomic resolution structures of tau, amyloid-β (Aβ), α-synuclein (α-syn), and transactive response element DNA-binding protein of 43 kDa (TDP-43) aggregates from a variety of diseases. Importantly, in vitro aggregate structures do not recapitulate ex vivo aggregate structures. Ex vivo tau aggregate structures indicate individual tauopathies have a consistent aggregate structure unique from other tauopathies. α-syn structures show that even within a disease, aggregate heterogeneity may correlate to disease course. Ex vivo structures have also provided insight into how posttranslational modifications may relate to aggregate structure. Though there is less cryo-EM data for human tissue-derived TDP-43 and Aβ, initial structural studies provide a basis for future endeavors. This review highlights structural variations across neurodegenerative diseases and reveals fundamental differences between experimental systems and human tissue derived protein inclusions.

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In Vitro Conversion Assays Diagnostic for Neurodegenerative Proteinopathies

The Journal of Applied Laboratory Medicine ◽

10.1373/jalm.2019.029801 ◽

2019 ◽

Vol 5 (1) ◽

pp. 142-157 ◽

Cited By ~ 1

Author(s):

Serena Singh ◽

Mari L DeMarco

Keyword(s):

Prion Protein ◽

Protein Misfolding ◽

Amyloid Β ◽

Intrinsic Property ◽

Transmissible Spongiform Encephalopathies ◽

Diagnostic Tools ◽

Clinical Implementation ◽

Spongiform Encephalopathies ◽

Further Development

Abstract Background In vitro conversion assays, including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) techniques, were first developed to study the conversion process of the prion protein to its misfolded, disease-associated conformation. The intrinsic property of prion proteins to propagate their misfolded structure was later exploited to detect subfemtogram quantities of the misfolded protein present in tissues and fluids from humans and animals with transmissible spongiform encephalopathies. Currently, conversion assays are used clinically as sensitive and specific diagnostic tools for antemortem diagnosis of prion disease. Content In vitro conversion assays are now being applied to the development of diagnostics for related neurodegenerative diseases, including detection of misfolded α-synuclein in Parkinson disease, misfolded amyloid-β in Alzheimer disease, and misfolded tau in Pick disease. Like the predicate prion protein in vitro conversion diagnostics, these assays exploit the ability of endogenously misfolded proteins to induce misfolding and aggregation of their natively folded counterpart in vitro. This property enables biomarker detection of the underlying protein pathology. Herein, we review RT-QuIC and PMCA for (a) prion-, (b) α-synuclein-, (c) amyloid-β-, and (d) tau-opathies. Summary Although already in routine clinical use for the detection of transmissible spongiform encephalopathies, in vitro conversion assays for other neurodegenerative disorders require further development and evaluation of diagnostic performance before consideration for clinical implementation.

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