Treatment of age-related decreases in GTP levels restores endocytosis and autophagy

Brewer GJ, Herrera RA, Philipp S, Sosna J, Reyes-Ruiz JM, Glabe CG. Age-related intraneuronal aggregation of amyloid-beta in endosomes, mitochondria, autophagosomes, and lysosomes. J Alzheimers Dis. 2020;73:229–46. https://doi.org/10.3233/JAD-190835.

Article  Google Scholar 

Brewer GJ. Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Exp Gerontol. 2010;45:173–9. https://doi.org/10.1016/j.exger.2009.11.007.

Article  Google Scholar 

Swerdlow RH. The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview. J Alzheimers Dis. 2023;92:751–68. https://doi.org/10.3233/JAD-221286.

Article  Google Scholar 

Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol. 2022;18:243–58. https://doi.org/10.1038/s41574-021-00626-7.

Article  Google Scholar 

Lopez FV, O’Shea A, Rosenberg JT, Leeuwenburgh C, Anton S, Bowers D, Woods AJ. Frontal adenosine triphosphate markers from (31)P MRS are associated with cognitive performance in healthy older adults: preliminary findings. Front Aging Neurosci. 2023;15:1180994. https://doi.org/10.3389/fnagi.2023.1180994.

Article  Google Scholar 

Ashford JW, Jarvik L. Alzheimer’s disease: does neuron plasticity predispose to axonal neurofibrillary degeneration? N Engl J Med. 1985;313:388–9.

Google Scholar 

Martinez RAS, Pinky PD, Harlan BA, Brewer GJ. GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease. Geroscience. 2023;45:757–80. https://doi.org/10.1007/s11357-022-00717-x.

Article  Google Scholar 

Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64:113–22.

Google Scholar 

Roebuck KA. Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB (Review). Int J Mol Med. 1999;4:223–30. https://doi.org/10.3892/ijmm.4.3.223.

Article  Google Scholar 

Chini CCS, Zeidler JD, Kashyap S, Warner G, Chini EN. Evolving concepts in NAD(+) metabolism. Cell Metab. 2021;33:1076–87. https://doi.org/10.1016/j.cmet.2021.04.003.

Article  Google Scholar 

Prolla TA, Denu JM. NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab. 2014;19:178–80. https://doi.org/10.1016/j.cmet.2014.01.005.

Article  Google Scholar 

Markesbery WR, Carney JM. Oxidative alterations in Alzheimer’s disease. Brain Pathol. 1999;9:133–46.

Google Scholar 

Tonnies E & Trushina E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. J Alzheimers Dis 2017;57:1105–21 https://doi.org/10.3233/JAD-161088

Brand MD. Riding the tiger - physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix. Crit Rev Biochem Mol Biol. 2020;55:592–661. https://doi.org/10.1080/10409238.2020.1828258.

Article  Google Scholar 

George M, Tharakan M, Culberson J, Reddy AP, Reddy PH. Role of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases. Ageing Res Rev. 2022;82:101756. https://doi.org/10.1016/j.arr.2022.101756.

Article  Google Scholar 

Ghosh D, Levault KR, Brewer GJ. Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species. Neurobiology of Aging. 2014;35:179–90. https://doi.org/10.1016/j.neurobiolaging.2013.06.023.

Article  Google Scholar 

Mokra D, Joskova M, Mokry J. Therapeutic Effects of Green Tea Polyphenol (-)-Epigallocatechin-3-Gallate (EGCG) in Relation to Molecular Pathways Controlling Inflammation, Oxidative Stress, and Apoptosis. Int J Mol Sci. 2022;24:340. https://doi.org/10.3390/ijms24010340.

Article  Google Scholar 

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer’s disease with plaques and tangles. Intracellular Abeta and Synaptic Dysfunction Neuron. 2003;39:409–21.

Google Scholar 

Brewer GJ, Torricelli JR. Isolation and culture of adult neurons and neurospheres. Nat Protoc. 2007;2:1490–8.

Google Scholar 

Bianchi-Smiraglia A, Rana MS, Foley CE, Paul LM, Lipchick BC, Moparthy S, Moparthy K, Fink EE, Bagati A, Hurley E, Affronti HC, Bakin AV, Kandel ES, Smiraglia DJ, Feltri ML, Sousa R, Nikiforov MA. Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution. Nat Methods. 2017;14:1003–9. https://doi.org/10.1038/nmeth.4404.

Article  Google Scholar 

Bianchi-Smiraglia A & Nikiforov MA. Assessment of Intracellular GTP Levels Using Genetically Encoded Fluorescent Sensors. Methods Mol Biol. 2022;2394:163–9. https://doi.org/10.1007/978-1-0716-1811-0_10

Pensalfini A, Albay R 3rd, Rasool S, Wu JW, Hatami A, Arai H, Margol L, Milton S, Poon WW, Corrada MM, Kawas CH, Glabe CG. Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol Dis. 2014;71:53–61. https://doi.org/10.1016/j.nbd.2014.07.011.

Article  Google Scholar 

Ward MW, Rego AC, Frenguelli BG, Nicholls DG. Mitochondrial Membrane Potential and Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells. J Neurosci. 2000;20:7208–19. https://doi.org/10.1523/JNEUROSCI.20-19-07208.2000.

Article  Google Scholar 

Butterfield DA, Boyd-Kimball D. Redox proteomics and amyloid beta-peptide: insights into Alzheimer disease. J Neurochem. 2019;151:459–87. https://doi.org/10.1111/jnc.14589.

Article  Google Scholar 

Ghosh D, Levault KR, Brewer GJ. Relative importance of redox buffers GSH and NAD(P)H in age-related neurodegeneration and Alzheimer disease-like mouse neurons. Aging Cell. 2014;13:631–40. https://doi.org/10.1111/acel.12216.

Article  Google Scholar 

Hajam YA, Rani R, Ganie SY, Sheikh TA, Javaid D, Qadri SS, Pramodh S, Alsulimani A, Alkhanani MF, Harakeh S, Hussain A, Haque S & Reshi MS. Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells. 2022;11. https://doi.org/10.3390/cells11030552

Li Y, Berliocchi L, Li Z, Rasmussen LJ. Interactions between mitochondrial dysfunction and other hallmarks of aging: Paving a path toward interventions that promote healthy old age. Aging Cell. 2024;23:e13942. https://doi.org/10.1111/acel.13942.

Article  Google Scholar 

Parihar MS, Brewer GJ. Amyloid-beta as a modulator of synaptic plasticity. J Alzheimers Dis. 2010;22:741–63. https://doi.org/10.3233/JAD-2010-101020.

Article  Google Scholar 

Dong Y, Digman MA, Brewer GJ. Age- and AD-related redox state of NADH in subcellular compartments by fluorescence lifetime imaging microscopy. Geroscience. 2019;41:51–67. https://doi.org/10.1007/s11357-019-00052-8.

Article  Google Scholar 

Zapata-Perez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD(+) homeostasis in human health and disease. EMBO Mol Med. 2021;13:e13943. https://doi.org/10.15252/emmm.202113943

Tonelli C, Chio IIC, Tuveson DA. Transcriptional Regulation by Nrf2. Antioxid Redox Signal. 2018;29:1727–45. https://doi.org/10.1089/ars.2017.7342.

Article  Google Scholar 

Hu J, Webster D, Cao J, Shao A. The safety of green tea and green tea extract consumption in adults - Results of a systematic review. Regul Toxicol Pharmacol. 2018;95:412–33. https://doi.org/10.1016/j.yrtph.2018.03.019.

Article  Google Scholar 

Baird L, Yamamoto M. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. Mol Cell Biol. 2020;40:e00099-20. https://doi.org/10.1128/MCB.00099-20.

Article  Google Scholar 

Singh B, Bhaskar S. Methods for Detection of Autophagy in Mammalian Cells. Methods Mol Biol. 2019;2045:245–58. https://doi.org/10.1007/7651_2018_190.

Article  Google Scholar 

Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA. 2001;98:7037–44.

Google Scholar 

Lebrand C, Corti M, Goodson H, Cosson P, Cavalli V, Mayran N, Faure J, Gruenberg J. Late endosome motility depends on lipids via the small GTPase Rab7. EMBO J. 2002;21:1289–300. https://doi.org/10.1093/emboj/21.6.1289.

Article  Google Scholar 

Bagshaw RD, Callahan JW, Mahuran DJ. The Arf-family protein, Arl8b, is involved in the spatial distribution of lysosomes. Biochem Biophys Res Commun. 2006;344:1186–91. https://doi.org/10.1016/j.bbrc.2006.03.221.

Article  Google Scholar 

Pontrello CG, McWhirt JM, Glabe CG, Brewer GJ. Age-related oxidative redox and metabolic changes precede intraneuronal amyloid-beta accumulation and plaque deposition in a transgenic alzheimer’s disease mouse model. J Alzheimers Dis. 2022;90:1501–21. https://doi.org/10.3233/JAD-220824.

Article  Google Scholar 

Butterfield DA, Reed T, Sultana R. Roles of 3-nitrotyrosine- and 4-hydroxynonenal-modified brain proteins in the progression and pathogenesis of Alzheimer’s disease. Free Radic Res. 2011;45:59–72. https://doi.org/10.3109/10715762.2010.520014.

Article  Google Scholar 

Nixon RA, Rubinsztein DC. Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2024;25:926–46. https://doi.org/10.1038/s41580-024-00757-5.

Article  Google Scholar 

Kelly G, Kataura T, Panek J, Ma G, Salmonowicz H, Davis A, Kendall H, Brookes C, Ayine-Tora DM, Banks P, Nelson G, Dobby L, Pitrez PR, Booth L, Costello L, Richardson GD, Lovat P, Przyborski S, Ferreira L, Greaves L, Szczepanowska K, von Zglinicki T, Miwa S, Brown M, Flagler M, Oblong JE, Bascom CC, Carroll B, Reynisson J, Korolchuk VI. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule. Dev Cell. 2024;59:1924-39 e7. https://doi.org/10.1016/j.devcel.2024.04.020.

Article  Google Scholar 

Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. https://doi.org/10.1038/nature08780.

Article  Google Scholar 

Minhas PS, Jones JR, Latif-Hernandez A, Sugiura Y, Durairaj AS, Wang Q, Mhatre SD, Uenaka T, Crapser J, Conley T, Ennerfelt H, Jung YJ, Liu L, Prasad P, Jenkins BC, Ay YA, Matrongolo M, Goodman R, Newmeyer T, Heard K, Kang A, Wilson EN, Yang T, Ullian EM, Serrano GE, Beach TG, Wernig M, Rabinowitz JD, Suematsu M, Longo FM, McReynolds MR, Gage FH, Andreasson KI. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies. Science. 2024;385:eabm6131.

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