Rationalising the role of Keratin 9 as a biomarker for Alzheimer’s disease

Richens, Joanna L.; Spencer, Hannah L.; Butler, Molly; Cantlay, Fiona; Vere, Kelly; Bajaj, Nin; Morgan, Kevin; O'Shea, Paul

doi:10.1038/srep22962

Cited by 26 publications

(17 citation statements)

References 90 publications

(87 reference statements)

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“…SCEL and MARCH10 are both linked to Alzheimer's disease. A specific type of keratin has been detected in the cerebrospinal fluid of patients with Alzheimer's disease but not healthy individuals, which may be the result of blood-brain barrier breakdown or dysregulation of the ubiquitin proteasome (36). Since SCEL is involved with cells which produce keratin and MARCH10 is a ubiquitin ligase, the SCEL and MARCH10 genes may play a role in the mechanism of keratin accumulation in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis Shows a Robust Host Response toToxoplasma gondiiduring Early and Late Chronic Infection in Both Male and Female Mice

2019

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The long-term host effects caused by the protozoan parasite Toxoplasma gondii are poorly understood. High-throughput RNA sequencing analysis previously determined that the host response in the brain was greater and more complex at 28 days than at 10 days postinfection. Here, we analyzed the host transcriptional profile of age- and sex-matched mice during very early (21 days), early (28 days), mid (3 months), and late (6 months) chronic infection. We found that a majority of the host genes which increase in abundance at day 21 postinfection are still increased at 6 months postinfection for both male and female mice. While most of the differentially expressed genes were similar between sexes, females had far fewer genes that were significantly less abundant, which may have led to the slightly increased cyst burden in males. Transcripts for C-X-C motif chemokine ligand 13 and a C-C motif chemokine receptor 2 (CCR2) were significantly higher in females than in males during infection. As T. gondii chronic infection and profilin (PRF) confer resistance to Listeria monocytogenes infection in a CCR2-dependent manner, the differences in CCR2 expression led us to retest the protection of PRF in both sexes. Male mice were nearly as effective as female mice at reducing the bacterial burden either with a chronic infection or when treated with PRF. These data show that most of the host genes differentially expressed in response to T. gondii infection are similar between males and females. While differences in transcript abundance exist between the sexes, the infection phenotypes tested here did not show significant differences.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis Shows a Robust Host Response toToxoplasma gondiiduring Early and Late Chronic Infection in Both Male and Female Mice

2019

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“…Notably, keratin 9 was identified by multiple research groups in the cerebrospinal fluid and has been even proposed as a biomarker for AD [151–153]. Furthermore, keratin 1 was identified in 5xFAD mouse hippocampi using proteomics [154], and keratin 1 and 9 show different expression patterns in other neurodegenerative disorders [155].…”

Section: Discussionmentioning

confidence: 99%

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Zolochevska

Bjorklund

Woltjer

et al. 2018

JAD

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Some individuals, here referred to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

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“…They also contribute in stress management, apoptosis and wound healing [ 52 ]. While few researchers described the presence of keratin in blood [ 53 , 54 ], little was revealed about the normal level of different keratins in blood, specially that in mouse and how they may impact the uptake of NPs by the organs.…”

Section: Discussionmentioning

confidence: 99%

Carbonate Apatite and Hydroxyapatite Formulated with Minimal Ingredients to Deliver SiRNA into Breast Cancer Cells In Vitro and In Vivo

Islam

Al-Busaidi

Zaman

et al. 2020

JFB

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Introduction: Cancer is one of the top-ranked noncommunicable diseases causing deaths to nine million people and affecting almost double worldwide in 2018. Tremendous advancement in surgery, chemotherapy, radiation and targeted immunotherapy have improved the rate of cure and disease-free survival. As genetic mutations vary in different cancers, potential of customized treatment to silence the problem gene/s at the translational level is being explored too. Yet delivering therapeutics at the required dosage only to the affected cells without affecting the healthy ones, is a big hurdle to be overcome. Scientists worldwide have been working to invent a smart drug delivery system for targeted delivery of therapeutics to tumor tissues only. As part of such an effort, few organic nanocarriers went to clinical trials, while inorganic nanoparticles (NPs) are still in development stage despite their many customizable properties. Carbonate apatite (CA), a pH sensitive nanocarrier has emerged as an efficient delivery system for drugs, plasmids and siRNAs in preclinical models of breast and colon cancers. Like hydroxyapatite (HA) which serves as a classical tool for delivery of genetic materials such as siRNA and plasmid, CA is an apatite-based synthetic carrier. We developed simplified methods of formulating CA-in-DMEM and a DMEM-mimicking buffer and HA in a HEPES-buffered solution and characterized them in terms of size, stability, protein corona (PC) composition, cytotoxicity, siRNA delivery efficiency in breast cancer cells and siRNA biodistribution profile in a mouse model of breast cancer. Methods: Particle growth was analyzed via spectrophotometry and light microscopy, size was measured via dynamic light scattering and scanning electron microscopy and confirmation of functional groups in apatite structures was made by FT-IR. siRNA-binding was analyzed via spectrophotometry. Stability of the formulation solutions/buffers was tested over various time points and at different temperatures to determine their compatibility in the context of practical usage. Cellular uptake was studied via fluorescence microscopy. MTT assay was performed to measure the cytotoxicity of the NPs. Liquid chromatography—mass spectrometry was carried out to analyze the PC formed around all three different NPs in serum-containing media. To explore biodistribution of all the formulations, fluorescence-labeled siRNA-loaded NPs were administered intravenously prior to analysis of fluorescence intensity in the collected organs and tumors of the treated mice. Results: The size of NPs in 10% serum-containing media was dramatically different where CA-in-DMB and HA were much larger than CA-in-DMEM. Effect of media was notable on the PC composition of all three NPs. All three NPs bound albumin and some common protease inhibitors involved in bone metabolism due to their compositional similarity to our bone materials. Moreover, CA also bound heme-binding proteins and opsonins. Unlike CA, HA bound different kinds of keratins. Difference in PC constitution was likely to influence accumulation of NPs in various organs including those of reticuloendothelial system, such as liver and spleen and the tumor. We found 10 times more tumor accumulation of CA-in-DMB than CA-in-DMEM, which could be due to more stable siRNA-binding and distinct PC composition of the former. Conclusion: As a nanocarrier CA is more efficient than HA for siRNA delivery to the tumor. CA prepared in a buffer containing only the mere constituents was potentially more efficient than classical CA prepared in DMEM, owing to the exclusion of interference attributed by the inorganic ions and organic molecules present in DMEM.

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Rationalising the role of Keratin 9 as a biomarker for Alzheimer’s disease

Cited by 26 publications

References 90 publications

Transcriptional Analysis Shows a Robust Host Response toToxoplasma gondiiduring Early and Late Chronic Infection in Both Male and Female Mice

Transcriptional Analysis Shows a Robust Host Response toToxoplasma gondiiduring Early and Late Chronic Infection in Both Male and Female Mice

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Carbonate Apatite and Hydroxyapatite Formulated with Minimal Ingredients to Deliver SiRNA into Breast Cancer Cells In Vitro and In Vivo

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