Nitric oxide donors rescue metabolic and mitochondrial dysfunction in obese Alzheimer's model.
Animals
Alzheimer Disease
/ metabolism
Obesity
/ metabolism
Mitochondria
/ metabolism
Mice
Nitric Oxide Donors
/ pharmacology
Disease Models, Animal
Female
Mice, Transgenic
Diet, High-Fat
/ adverse effects
Hypothalamus
/ metabolism
Energy Metabolism
/ drug effects
Insulin Resistance
Nitric Oxide
/ metabolism
Citrulline
/ pharmacology
Sodium Nitrite
/ pharmacology
Humans
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 10 2024
30 10 2024
Historique:
received:
12
03
2024
accepted:
08
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer's disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology.
Identifiants
pubmed: 39478095
doi: 10.1038/s41598-024-75870-8
pii: 10.1038/s41598-024-75870-8
doi:
Substances chimiques
Nitric Oxide Donors
0
Nitric Oxide
31C4KY9ESH
Citrulline
29VT07BGDA
Sodium Nitrite
M0KG633D4F
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26118Informations de copyright
© 2024. The Author(s).
Références
Scheffer, S., Hermkens, D. M. A., Van Der Weerd, L., De Vries, H. E. & Daemen, M. J. A. P. Vascular hypothesis of Alzheimer Disease: Topical review of mouse models. Arterioscler. Thromb. Vasc Biol. 1265–1283. https://doi.org/10.1161/ATVBAHA.120.311911 (2021).
Kivipelto, M. et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol. 62, 1556–1560 (2005).
doi: 10.1001/archneur.62.10.1556
pubmed: 16216938
Dove, A. et al. Cardiometabolic multimorbidity accelerates cognitive decline and dementia progression. Alzheimer’s Dement. https://doi.org/10.1002/ALZ.12708 (2022).
doi: 10.1002/ALZ.12708
Austin, S. A., Santhanam, A. V., Hinton, D. J., Choi, D. S. & Katusic, Z. S. Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J. Neurochem. 127, 691–700 (2013).
doi: 10.1111/jnc.12334
pubmed: 23745722
pmcid: 3825764
De La Torre, J. C. & Stefano, G. B. Evidence that Alzheimer’s disease is a microvascular disorder: The role of constitutive nitric oxide. Brain Res. Rev. 34, 119–136 (2000).
doi: 10.1016/S0165-0173(00)00043-6
pubmed: 11113503
De La Monte, S. M., Sohn, Y. K., Etienne, D., Kraft, J. & Wands, J. R. Role of aberrant nitric oxide synthase-3 expression in cerebrovascular degeneration and vascular-mediated injury in Alzheimer’s disease. Ann. N Y Acad. Sci. 903, 61–71 (2000).
doi: 10.1111/j.1749-6632.2000.tb06351.x
pubmed: 10818490
Nisoli, E. et al. Mitochondrial biogenesis in mammals: The role of endogenous nitric oxide. Sci. (80-). 299, 896–899 (2003).
doi: 10.1126/science.1079368
Cenini, G. & Voos, W. Mitochondria as potential targets in Alzheimer disease therapy: An update. Front. Pharmacol. 10, 1–20 (2019).
doi: 10.3389/fphar.2019.00902
Toda, N. & Okamura, K. A. Obesity-Induced Cerebral Hypoperfusion derived from endothelial dysfunction: One of the risk factors for Alzheimer’s Disease. Curr. Alzheimer Res. 11, 733–744 (2014).
doi: 10.2174/156720501108140910120456
pubmed: 25212912
Anstey, K. J., Cherbuin, N., Budge, M. & Young, J. Body mass index in midlife and late-life as a risk factor for dementia: A meta-analysis of prospective studies. Obes. Rev. 12, 426–437 (2011).
doi: 10.1111/j.1467-789X.2010.00825.x
Nepal, B., Brown, L. J. & Anstey, K. J. Rising midlife obesity will worsen future prevalence of dementia. PLoS One 9, (2014).
McDuff, T. & Sumi, S. M. Subcortical degeneration in Alzheimer’s disease. Neurology. 35, 123–126 (1985).
doi: 10.1212/WNL.35.1.123
pubmed: 3917560
Saper, C. B. & German, D. C. Hypothalamic pathology in Alzheimer’s disease. Neurosci. Lett. 74, 364–370 (1987).
doi: 10.1016/0304-3940(87)90325-9
pubmed: 2436113
Schultz, C., Ghebremedhin, E., Braak, H. & Braak, E. Neurofibrillary pathology in the human paraventricular and supraoptic nuclei. Acta Neuropathol. 94, 99–102 (1997).
doi: 10.1007/s004010050679
pubmed: 9224538
Jin, S. & Diano, S. Mitochondrial dynamics and hypothalamic regulation of metabolism. Endocrinology. 159, 3596–3604 (2018).
doi: 10.1210/en.2018-00667
pubmed: 30203064
Sakamuri, S. S. V. P. et al. Nitric oxide synthase inhibitors negatively regulate respiration in isolated rodent cardiac and brain mitochondria. Am. J. Physiol. Heart Circ. Physiol. 318, H295–H300 (2020).
doi: 10.1152/ajpheart.00720.2019
pubmed: 31922888
Han, C., Zhao, Q. & Lu, B. The role of nitric oxide signaling in food intake; insights from the inner mitochondrial membrane peptidase 2 mutant mice. Redox Biol. 1, 498–507 (2013).
doi: 10.1016/j.redox.2013.10.003
pubmed: 24251118
Gyengesi, E., Paxinos, G. & Andrews, Z. B. Oxidative stress in the Hypothalamus: The importance of Calcium Signaling and mitochondrial ROS in Body Weight Regulation. Curr. Neuropharmacol. 10, 344–353 (2012).
doi: 10.2174/157015912804499438
pubmed: 23730258
Hamilton, A. & Holscher, C. The effect of ageing on neurogenesis and oxidative stress in the APP swe/PS1 deltaE9 mouse model of Alzheimer’s disease. Brain Res. 1449, 83–93 (2012).
doi: 10.1016/j.brainres.2012.02.015
pubmed: 22418058
Ahmed, S. et al. Partial endothelial nitric oxide synthase deficiency exacerbates cognitive deficit and amyloid pathology in the APPswe/PS1∆E9 mouse model of Alzheimer’s Disease. Int. J. Mol. Sci. 23, (2022).
Bergin, D. et al. Altered plasma arginine metabolome precedes behavioural and brain arginine metabolomic profile changes in the APPswe/PS1∆E9 mouse model of Alzheimer’s disease. Transl Psychiatry 8, (2018).
Leuner, K., Müller, W. E. & Reichert, A. S. From mitochondrial dysfunction to amyloid beta formation: Novel insights into the pathogenesis of Alzheimer’s disease. Mol. Neurobiol. 46, 186–193 (2012).
doi: 10.1007/s12035-012-8307-4
pubmed: 22833458
Walker, J. M. & Harrison, F. E. Shared neuropathological characteristics of obesity, type 2 diabetes and Alzheimer’s disease: Impacts on cognitive decline. Nutrients. 7, 7332–7357 (2015).
doi: 10.3390/nu7095341
pubmed: 26340637
Asiimwe, N., Yeo, S. G., Kim, M. S., Jung, J. & Jeong, N. Y. Nitric oxide: Exploring the contextual link with Alzheimer’s disease. Oxid. Med. Cell. Longev. (2016). (2016).
Thériault, P., ElAli, A. & Rivest, S. High fat diet exacerbates Alzheimer’s disease-related pathology in APPswe/PS1 mice. Oncotarget. 7, 67808–67827 (2016).
doi: 10.18632/oncotarget.12179
pubmed: 27661129
Bracko, O. et al. High fat diet worsens Alzheimer’s disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, but not by synergistically decreasing cerebral blood flow. Sci. Rep. 10, 1–16 (2020).
doi: 10.1038/s41598-020-65908-y
Ettcheto, M. et al. Evaluation of neuropathological effects of a high-fat diet in a presymptomatic alzheimer’s disease stage in APP/PS1 mice. J. Alzheimers Dis. 54, 233–251 (2016).
doi: 10.3233/JAD-160150
pubmed: 27567882
Lee, Y. H. et al. Augmented insulin and leptin resistance of high fat diet-fed APPswe/PS1dE9 transgenic mice exacerbate obesity and glycemic dysregulation. Int. J. Mol. Sci. 19, (2018).
Cau, S. B. A., Carneiro, F. S. & Tostes, R. C. Differential modulation of nitric oxide synthases in aging: Therapeutic opportunities. Front. Physiol. 3 JUN, (2012).
Zou, Y., Wang, Q. & Cheng, X. Causal relationship between basal metabolic rate and Alzheimer’s Disease: Abidirectional two-sample mendelian randomization study. Neurol. Ther. 12, 763–776 (2023).
doi: 10.1007/s40120-023-00458-9
pubmed: 36894827
pmcid: 10195958
Doorduijn, A. S. et al. Energy intake and expenditure in patients with Alzheimer’s disease and mild cognitive impairment: The NUDAD project. Alzheimer’s Res. Ther. 12, 1–8 (2020).
Poehlman, E. T. & Dvorak, R. V. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am. J. Clin. Nutr. 71, 650S–655S (2000).
doi: 10.1093/ajcn/71.2.650s
pubmed: 10681274
Zou, D. et al. Single-cell and spatial transcriptomics reveals that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in Alzheimer’s disease. Pharmacol. Res. 201, 107098 (2024).
doi: 10.1016/j.phrs.2024.107098
pubmed: 38325728
Reid, D. M. et al. Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease. Sci. Rep. 13, 1–15 (2023).
doi: 10.1038/s41598-023-41190-6
Giannos, P., Prokopidis, K., Raleigh, S. M., Kelaiditi, E. & Hill, M. Altered mitochondrial microenvironment at the spotlight of musculoskeletal aging and Alzheimer’s disease. Sci. Rep. 12, 1–8 (2022).
doi: 10.1038/s41598-022-15578-9
Leyh, J. et al. Long-term diet-induced obesity does not lead to learning and memory impairment in adult mice. PLoS ONE 16, (2021).
Osiecka, Z. et al. Obesity reduces hippocampal structure and function in older African americans with the APOE-ε4 Alzheimer’s disease risk allele. Front. Aging Neurosci. 15, (2023).
Letra, L., Santana, I. & Seiça, R. Obesity as a risk factor for Alzheimer’s disease: The role of adipocytokines. Metab. Brain Dis. 29, 563–568 (2014).
doi: 10.1007/s11011-014-9501-z
pubmed: 24553879
Zheng, H. et al. The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer’s disease. Biochim. Biophys. Acta - Mol. Basis Dis. 1864, 263–273 (2018).
doi: 10.1016/j.bbadis.2017.10.028
pubmed: 29107091
Cunarro, J., Casado, S., Lugilde, J. & Tovar, S. Hypothalamic mitochondrial dysfunction as a target in obesity and metabolic disease. Front. Endocrinol. (Lausanne). 9, 1–10 (2018).
doi: 10.3389/fendo.2018.00283
Cifuentes, D. et al. Inactivation of nitric oxide synthesis exacerbates the development of Alzheimer Disease Pathology in APPPS1 mice (amyloid precursor Protein/Presenilin-1). Hypertens. (Dallas Tex. 1979). 70, 613–623 (2017).
doi: 10.1161/HYPERTENSIONAHA.117.09742
Anjum, I., Fayyaz, M., Wajid, A., Sohail, W. & Ali, A. Does obesity increase the risk of dementia: A literature review. Cureus 10, (2018).
Scheyer, O. et al. Female sex and Alzheimer’s risk: The menopause connection. J. Prev. Alzheimer’s Dis. 5, 225–230 (2018).
Castro-Aldrete, L. et al. Sex and gender considerations in Alzheimer’s disease: The women’s Brain Project contribution. Front. Aging Neurosci. 15, 1–12 (2023).
doi: 10.3389/fnagi.2023.1105620
Powers, R. et al. L-Citrulline administration increases the arginine/ADMA ratio, decreases blood pressure and improves vascular function in obese pregnant women. Pregnancy Hypertens. https://doi.org/10.1016/j.preghy.2014.10.011 (2015).
doi: 10.1016/j.preghy.2014.10.011
Schwedhelm, E. et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: Impact on nitric oxide metabolism. Br. J. Clin. Pharmacol. 65, 51–59 (2008).
doi: 10.1111/j.1365-2125.2007.02990.x
pubmed: 17662090
Bryan, N. S. Nitrite in nitric oxide biology: Cause or consequence? A systems-based review. Free Radic. Biol. Med. https://doi.org/10.1016/j.freeradbiomed.2006.05.019 (2006).
doi: 10.1016/j.freeradbiomed.2006.05.019
pubmed: 16895789
Bryan, N. S. et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat. Chem. Biol. https://doi.org/10.1038/nchembio734 (2005).
doi: 10.1038/nchembio734
pubmed: 16408059
Jéquier, E., Acheson, K. & Schutz, Y. Assessment of energy expenditure and fuel utilization in man. Annu. Rev. Nutr. https://doi.org/10.1146/annurev.nu.07.070187.001155 (1987).
doi: 10.1146/annurev.nu.07.070187.001155
pubmed: 3300732
King, A. L. et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc. Natl. Acad. Sci. U S A. https://doi.org/10.1073/pnas.1321871111 (2014).
doi: 10.1073/pnas.1321871111
pubmed: 25422467
Dawid, C. et al. Comparative assessment of purified saponins as permeabilization agents during respirometry. Biochim. Biophys. Acta Bioenerg. 1861, 148251 (2020).
doi: 10.1016/j.bbabio.2020.148251
pubmed: 32598881