The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple‐transgenic Alzheimer's disease model mice

Lin, Kuan Ho; Chiu, Chih Hao; Kuo, Wei Wen; Ju, Da‐Tong; Shen, Chia Yao; Chen, Ray Jade; Lin, Chien Chung; Viswanadha, Vijaya Padma; Liu, Jian Sheng; Huang, Chih Yang

doi:10.1002/tox.22498

Cited by 15 publications

(13 citation statements)

References 55 publications

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“…Because the pathology of myocardial tissue in AD is multi-faceted, disturbances in calcium homeostasis accompanied with Aβ inclusions39 are known to contribute to LV dysfunction. Increased interstitial space, cardiomyocyte disarray, decreased anti-apoptosis proteins, and elevated cytochrome C and caspase-9 expression recently reported in 3xTg mice could also lead to impaired function. 57 …”

Section: Discussionmentioning

confidence: 88%

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>

Esfandiarei¹,

Hoxha²,

Talley³

et al. 2019

DDDT

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Background: Studies have indicated an association between Alzheimer’s disease (AD) and increased risk of developing cardiovascular complications. Lifestyle modifiable factors, such as exercise and diet, are known to prevent cardio-cerebral disease. Recent studies demonstrate that hearts from early onset triple-transgenic AD mice exhibit pathologies, but it is not clear whether cardiovascular function is altered in this model. Methods: In this study, we measured in vivo cardiovascular function in 7-month-old male 3xTg mice and age-matched wild-type (WT) mice using high-frequency high-resolution ultrasound imaging. Results: Our findings indicated that aortic root measurements and interventricular septal dimensions were similar in 3xTg and wild-type mice. Systolic function, expressed as ejection fraction and fractional shortening, were decreased in 3xTg mice. Late (A) ventricular filling velocities, the early/atrial (E/A) ratio, and mitral valve deceleration time, all indices of diastolic function, were increased in 3xTg mice compared to WT mice. Treadmill exercise training and resveratrol supplementation in the diet for 5 months improved ejection fraction, fractional shortening, and restored diastolic deceleration times. Pulse wave velocity was ~33% higher in 3xTg, and accompanied by a significant increase in elastin fiber fragmentation within the aortic wall, which was associated with decrease in elastin content and fiber length. Aortic wall and adventitia thickness were increased in 3xTg mice compared to the WT group. Exercise training and resveratrol supplementation, or both, improved overall aortic morphology with no change in pulse wave velocity. Conclusion: Taken together, the results indicate that the aberrations in cardiac function and aortic elastin morphology observed in the 3xTg mouse model of AD can be prevented with exercise training and treatment with resveratrol. The benefits of regular exercise training and resveratrol supplementation of heart and aortic structure in the 3xTg mouse support the value of healthy lifestyle factors on cardiovascular health.

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Section: Discussionmentioning

confidence: 88%

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>

Esfandiarei¹,

Hoxha²,

Talley³

et al. 2019

DDDT

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“…Epigenetic drugs are chemicals or bioproducts that target regulatory components of the epigenetic machinery [18]. Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues for the treatment of major problems of health [11,19,138,150,151,152,153,154,155,156,157,158,159,160,161]. Within this growing category of drugs, several inhibitors of histone deacetylation and DNA methylation have been approved by the US FDA for hematological malignancies, and some epigenetic drugs are being evaluated in clinical trials for the treatment of several diseases [18].…”

Section: Pharmacoepigenetics Of Sirtuin Modulators and Epigenetic mentioning

confidence: 99%

“…Folic acid is cardio- and neuro-protective in early-stage AD in transgenic mice. Folic acid treatment restores SIRT1 expression, which is suppressed in 3×Tg mice, through enhanced AMPK expression [160].…”

Section: Pharmacoepigenetics Of Sirtuin Modulators and Epigenetic mentioning

confidence: 99%

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

Cacabelos

Carril

Cacabelos

et al. 2019

IJMS

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Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.

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“…Four-month-old homozygous 3xTg-AD mice and age matched male C57BL/6 mice were used as non-transgenic controls (Non-Tg) in all experiments. C57BL/6 mice are wildly accepted as the non-transgenic controls of 3xTg-AD mice (Lin et al 2018), , (Janelsins et al 2005), (Baek et al 2016).…”

Section: Strains Of Mice and Treatmentmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple‐transgenic Alzheimer's disease model mice

Cited by 15 publications

References 55 publications

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

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The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple‐transgenic Alzheimer's disease model mice

Cited by 15 publications

References 55 publications

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer&rsquo;s disease</p>

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer&rsquo;s disease</p>

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Contact Info

Product

Resources

About

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>

<p>Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease</p>