On the Stability of Messenger RNA and Ribosomal RNA in the Brains of Control Human Subjects and Patients with Alzheimer's Disease

1992 ◽  
Vol 58 (5) ◽  
pp. 1810-1819 ◽  
Author(s):  
B. M. Ross ◽  
J. T. Knowler ◽  
J. McCulloch
Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1626
Author(s):  
Line Séguy ◽  
Léna Guyon ◽  
Manon Maurel ◽  
Pascal Verdié ◽  
Audrey Davis ◽  
...  

Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.


Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2071
Author(s):  
Syed Sayeed Ahmad ◽  
Meetali Sinha ◽  
Khurshid Ahmad ◽  
Mohammad Khalid ◽  
Inho Choi

Alzheimer’s disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (−6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8–rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer’s potential against caspase 8.


2016 ◽  
Vol 113 (45) ◽  
pp. 12820-12825 ◽  
Author(s):  
Yujiang Wang ◽  
Joe Necus ◽  
Marcus Kaiser ◽  
Bruno Mota

The folding of the cortex in mammalian brains across species has recently been shown to follow a universal scaling law that can be derived from a simple physics model. However, it was yet to be determined whether this law also applies to the morphological diversity of different individuals in a single species, in particular with respect to factors, such as age, sex, and disease. To this end, we derived and investigated the cortical morphology from magnetic resonance images (MRIs) of over 1,000 healthy human subjects from three independent public databases. Our results show that all three MRI datasets follow the scaling law obtained from the comparative neuroanatomical data, which strengthens the case for the existence of a common mechanism for cortical folding. Additionally, for comparable age groups, both male and female brains scale in exactly the same way, despite systematic differences in size and folding. Furthermore, age introduces a systematic shift in the offset of the scaling law. In the model, this shift can be interpreted as changes in the mechanical forces acting on the cortex. We also applied this analysis to a dataset derived from comparable cohorts of Alzheimer’s disease patients and healthy subjects of similar age. We show a systematically lower offset and a possible change in the exponent for Alzheimer’s disease subjects compared with the control cohort. Finally, we discuss implications of the changes in offset and exponent in the data and relate it to existing literature. We, thus, provide a possible mechanistic link between previously independent observations.


1988 ◽  
Vol 3 (3) ◽  
pp. 255-261 ◽  
Author(s):  
D.R.Crapper Mclachlan ◽  
W.J. Lukiw ◽  
L. Wong ◽  
C. Bergeron ◽  
N.T. Bech-Hansen

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Jihong Xu ◽  
Steven W. Barger ◽  
Paul D. Drew

Accumulation of amyloid-βpeptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβdeposits has been placed in strategies involving immunization against the Aβpeptide. Initial Aβimmunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically,CD4+Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβimmunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γagonist 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γagonists may be effective in modulating the development of AD.


2019 ◽  
Author(s):  
Helen Zong Ying Wu ◽  
Anbupalam Thalamuthu ◽  
Lesley Cheng ◽  
Christopher Fowler ◽  
Colin L Masters ◽  
...  

Abstract Background: Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer’s disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging defined AD and normal cognition. Methods: Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher’s exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function. Results: After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p<0.05). Two of these miRNAs, miR-146b-5p and miR-15b-5p, were also significant in the replication cohort. Pathways analysis showed these miRNAs to be involved in innate immune system and regulation of the cell cycle respectively, both of which have relevance to AD pathogenesis. Conclusion: Blood miR-146b-5p and miR15b-5p showed consistent differential expression in AD compared to controls. Further replication and translational studies in strictly phenotyped cohorts are needed to establish their role as biomarkers for AD to have clinical utility.


2021 ◽  
Vol 15 ◽  
Author(s):  
Yuanyuan Liang ◽  
Lin Wang

Alzheimer’s disease (AD) is the most common cause of senile dementia. Although AD research has made important breakthroughs, the pathogenesis of this disease remains unclear, and specific AD diagnostic biomarkers and therapeutic strategies are still lacking. Recent studies have demonstrated that neuroinflammation is involved in AD pathogenesis and is closely related to other health effects. MicroRNAs (miRNAs) are a class of endogenous short sequence non-coding RNAs that indirectly inhibit translation or directly degrade messenger RNA (mRNA) by specifically binding to its 3′ untranslated region (UTR). Several broadly expressed miRNAs including miR-21, miR-146a, and miR-155, have now been shown to regulate microglia/astrocytes activation. Other miRNAs, including miR-126 and miR-132, show a progressive link to the neuroinflammatory signaling. Therefore, further studies on these inflamma-miRNAs may shed light on the pathological mechanisms of AD. The differential expression of inflamma-miRNAs (such as miR-29a, miR-125b, and miR-126-5p) in the peripheral circulation may respond to AD progression, similar to inflammation, and therefore may become potential diagnostic biomarkers for AD. Moreover, inflamma-miRNAs could also be promising therapeutic targets for AD treatment. This review provides insights into the role of inflamma-miRNAs in AD, as well as an overview of general inflamma-miRNA biology, their implications in pathophysiology, and their potential roles as biomarkers and therapeutic targets.


2020 ◽  
Vol 52 (3) ◽  
pp. 133-142
Author(s):  
Lucas A. C. Souza ◽  
Fatima Trebak ◽  
Veena Kumar ◽  
Ryousuke Satou ◽  
Patrick G. Kehoe ◽  
...  

High salt (sodium) intake leads to the development of hypertension despite the fact that plasma sodium concentration ([Na+]) is usually normal in hypertensive human patients. Increased cerebrospinal fluid (CSF) sodium contributes to elevated sympathetic activity and high blood pressure (BP) in rodent models of hypertension. However, whether there is an increased accumulation of sodium in the CSF of humans with chronic hypertension is not well defined. Here, we investigated CSF [Na+] from hypertensive and normotensive human subjects with family histories of Alzheimer’s disease in samples collected in a clinical trial, as spinal tap is not a routine clinical procedure for hypertensive patients. The [Na+] and osmolality in plasma and CSF were measured by flame photometry. Daytime ambulatory BP was monitored while individuals were awake. Participants were deidentified and data were analyzed in conjunction with a retrospective analysis of patient history and diagnosis. We found that CSF [Na+] was significantly higher in participants with high BP compared with normotensive participants; there was no difference in plasma [Na+], or plasma and CSF osmolality between groups. Subsequent multiple linear regression analyses controlling for age, sex, race, and body mass index revealed a significant positive correlation between CSF [Na+] and BP but showed no correlation between plasma [Na+] and BP. In sum, CSF [Na+] was higher in chronic hypertensive individuals and may play a key role in the pathogenesis of human hypertension. Collectively, our findings provide evidence for the clinical significance of CSF [Na+] in chronic hypertension in humans.


2013 ◽  
Vol 110 (10) ◽  
pp. 1751-1759 ◽  
Author(s):  
R. Chouinard-Watkins ◽  
C. Rioux-Perreault ◽  
M. Fortier ◽  
J. Tremblay-Mercier ◽  
Y. Zhang ◽  
...  

Carrying the apoE ε4 allele (E4+) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4 − ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance inn-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+v.E4 − . A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4 − . In E4+, mean plasma [13C]DHA was 31 % lower than that in E4 − , and cumulative β-oxidation of [13C]DHA was higher than that in E4 −  1–28 d post-dose (P≤ 0·05). A genotype × time interaction was detected for cumulative β-oxidation of [13C]DHA (P≤ 0·01). The whole-body half-life of [13C]DHA was 77 % lower in E4+ compared with E4 −  (P≤ 0·01). In E4+ and E4 − , the percentage dose of [13C]DHA recovered/h as13CO2correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4+ compared with E4 −  (P≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of13C-labelled fatty acids other than DHA cannot be deduced from the present study.


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