scholarly journals HYPERTENSION DOES NOT CONTRIBUTE TO MICROBLEEDS ONSET IN FEMALE EFAD MICE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S93-S93
Author(s):  
Mafalda Cacciottolo ◽  
Todd E Morgan ◽  
Caleb E Finch
Keyword(s):  
Blood Pressure ◽  
Alzheimer Disease ◽  
Mouse Model ◽  
Age Changes ◽  
Clinical Burden ◽  
Longitudinal Measurements ◽  
Age Related ◽  
Amyloid Deposits ◽  
Tail Cuff

Abstract Cerebral microbleeds (MBs) contribute to pre-clinical cognitive decline and are an additional clinical burden in Alzheimer Disease (AD). Hypertension is associated with MBs, with nearly 2-fold higher likelihood for MBs per SD increment in blood pressure (BP). We investigated the possible role of age-related hypertension in the EFAD mouse model (transgenic for carrying familial AD mutations and targeted replacement of human APO-E3 or -E4). MBs were detected by Prussian Blue histochemistry. We extended prior findings with observations that MBs arise early in life, by 2 months, and confirmed female excess for ApoE3 and-E4 carriers. Wildtype C57BL/6J mice also accumulated MBs, and a 10-fold lower level and more slowly up to 21mo of age. BP was measured by the tail-cuff method. All mice had BP in the normotensive range, <150 mm Hg, systolic. Longitudinal measurements of blood pressure at ages 2, 4, and 6 months showed few age changes, except for E3FAD females at 6 months (systolic, +20%, p<0.05; diastolic, +33%, p<0.05). A possible decrease in blood pressure was observed in EFAD mice (-33%, p<0.01) compared to C57BL/6J mice. A not statistical trend of increase was observed in older C57BL/6J mice up to 18 mo of age, consistent with previous reports. Older ages are required for complete negation of role of hypertension in the MB model. Ongoing studies will examine mice older than 6 months for potential relations of blood pressure and MB, and in relation to brain amyloid deposits which surrounded MBs in our prior study.

scholarly journals The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease

Channels ◽  
2014 ◽  
Vol 8 (3) ◽  
pp. 230-242 ◽  
Author(s):  
Jie Liu ◽  
Charlene Supnet ◽  
Suya Sun ◽  
Hua Zhang ◽  
Levi Good ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Mouse Model ◽  
Ryanodine Receptor ◽  
Receptor Type ◽  
Type 3

P4-029: The role of the renin-angiotensin system and apolipoprotein e in a sporadic Alzheimer disease mouse model

2015 ◽  
Vol 11 (7S_Part_17) ◽  
pp. P776-P776
Author(s):  
Christopher John De Vera ◽  
Andrew Ho ◽  
Monica Castro ◽  
Carleton B. Jones ◽  
T. Bucky Jones
Keyword(s):  
Alzheimer Disease ◽  
Mouse Model ◽  
Apolipoprotein E ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Sporadic Alzheimer Disease

scholarly journals Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea and creatinine variations in patients with dementia due to Alzheimer disease

2016 ◽  
pp. 76-80 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Juliana Marília Berretta ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Alzheimer Disease ◽  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitors ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Blood Levels ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Age Related

Background: Renal function declines according to age and vascular risk factors, whereas few data are available regarding genetically-mediated effects of anti-hypertensives over renal function. Objective: To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Methods: Consecutive outpatients older than 60 years-old with AD and no history of kidney transplant or dialytic therapy were recruited for prospective correlations regarding variations in fasting blood levels of urea and creatinine in one year, considering ACE genotypes of rs1800764 and rs4291 and their respective haplotypes, and treatment with ACEis along with blood pressure variations. Results: For 190 patients, 152 had arterial hypertension, and 122 used ACEis. Minor allele frequencies were 0.492 for rs1800764-C and 0.337 for rs4291-T, both in Hardy-Weinberg equilibrium. There were no overall significant yearly variations in levels of urea and creatinine, but their concurrent variations were positively correlated (ρ <0.0001). Each A allele of rs4291 led to an yearly urea increase of 3.074 mg/dL, and an yearly creatinine increase of 0.044 mg/dL, while the use of ACEis was protective regarding creatinine variations. The use of ACEis was also protective for carriers of rs1800764-CT/rs4291-AA, while carriers of rs1800764-CT/rs4291-AT had steeper reductions in creatinine levels, particularly when they were treated with ACEis. Conclusions: Effects of ACEis over creatinine variations are genetically mediated and independent of blood pressure variations in older people with AD.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julia Schewe ◽  
Eric Seidel ◽  
Sofia Forslund ◽  
Lajos Marko ◽  
Jörg Peters ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Oscillatory Activity ◽  
Type Ii ◽  
Mild Form ◽  
Familial Hyperaldosteronism ◽  
Aldosterone Production ◽  
Knockout Model ◽  
Knockin Mouse

AbstractGain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model (Clcn2−/−), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.

scholarly journals Characterization of a Mouse Model of Inducible Frailty: The Humanized IL-6 Mouse

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 532-532
Author(s):  
Lolita Nidadavolu ◽  
Peter M Abadir ◽  
Jeremy D Walston ◽  
Anne Le ◽  
Gayane Yenokyan ◽  
...  
Keyword(s):  
Body Temperature ◽  
Mouse Model ◽  
Basal Body ◽  
Basal Body Temperature ◽  
Frailty Phenotype ◽  
Age Related ◽  
Physical Testing ◽  
Before And After

Abstract The cytokine interleukin-6 (IL-6) has pleiotropic effects in aging and is elevated in frail older adults. We have developed a conditional mouse model to better characterize the role of IL-6 in promoting frailty and age-related mitochondrial dysregulation. The human IL-6 (hIL-6) knock-in mouse (TetO-hIL6) was developed utilizing CRISPR/Cas9 technology with transgene donor vector containing a tetracycline response element promoter driving expression of hIL-6 cDNA. Male TetO-hIL6 mice were treated with doxycycline-containing water for six weeks starting at 8 months old. RNAseq analysis of whole blood demonstrated significant upregulation of pro-inflammatory related markers at 6 weeks compared to baseline and upregulated cell proliferation and metabolism pathways. Physical testing of TetO-hIL6 mice before and after hIL-6 induction demonstrated decreased grip strength (p =0.003), decreased running capacity (p = 0.02), and 40% increase in falls off of the treadmill (p = 0.001). Induced mice also demonstrated decreased basal body temperature (p &lt; 0.001). Given the significant dysregulation of metabolism-related genes in RNAseq analysis and changes in basal body temperature following hIL-6 induction, we next performed untargeted metabolomics on plasma from mice at baseline and 6 weeks post-induction to better evaluate metabolic changes associated with hIL-6 elevation. We found changes in key serum metabolites, including circulating adenosine triphosphate (56% reduction, p = 0.02), pyruvate (35% reduction, p = 0.0006), alpha-ketoglutarate (47% reduction, p = 0.04), and succinate (306% increase, p = 0.001). The TetO-hIL6 mouse model allows for induction of hIL-6 at various timepoints across the lifespan and demonstrates features of a frailty phenotype.

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