Effects of Amino Acids and Their Mechanisms in Alzheimer’s Disease: Narrative Review
Sažetak
Alzheimer's disease is the most common form of dementia, a complex and progressive neurodegenerative disorder that slowly decreases memory, thinking skills and the ability to perform the simplest tasks. It is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). In the human body, amino acids are a source of metabolites and neurotransmitters. Various studies have also proven their association with Alzheimer's disease. Therefore, the research was conducted to review the effects of amino acids and their mechanisms on Alzheimer's disease. This descriptive study is a narrative review of articles on in vivo and in vitro amino acid-induced Alzheimer’s disease in the PubMed and ScienceDirect databases. The selected papers were in English, topic-relevant and published from 2011 to 2021 in journals of Q1, Q2 or Q3 category according to the Scimago Journal & Country Rank. The search yielded 27 relevant articles, but only 22 with 12 types of amino acids were included. Amino acids with positive effects were glutamine, d-serine, selenomethionine, s-adenosylmethionine, d-ribose-l-cysteine, s-allyl-cysteine, N-acetylcysteine, Se-methyl-selenocysteine and l-theanine, whereas some negative results come from homocysteine and N-methylamino-L-alanine. While taurine generally has a positive effect, there is a mechanism that negatively influences Alzheimer's disease. These amino acids are involved in all parts of the pathophysiology mechanism of Alzheimer's disease differently. The mechanisms include preventing (positive impact) or inducing (negative impact) mitochondrial dysfunction, inflammation, oxidative stress, formation of oligomers/plaque Aβ, tau hyperphosphorylation and neuronal/synaptic damage. Thus, not all amino acids have the activity of preventing/treating Alzheimer's disease.
Reference
Fakhoury M. Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr Neuropharmacol. 2018;16(5):508-518. doi: 10.2174/1570159X15666170720095240.
Gettman L. Lecanemab-irmb (Leqembi™) for Treatment of Alzheimer's disease. Sr Care Pharm. 2024 Feb 1;39(2):75-7. doi: 10.4140/TCP.n.2024.75.
Lacosta AM, Insua D, Badi H, Pesini P, Sarasa M. Neurofibrillary tangles of Aβx-40 in Alzheimer’s disease brains. J Alzheimers Dis. 2017;58(3):661-7. doi: 10.3233/JAD-170163.
GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022 Feb;7(2):e105-e125. doi: 10.1016/S2468-2667(21)00249-8.
Demirci M, Kadirhan OA. What we have learned to date from the omics approach to non-Alzheimer’s dementias. J Integr Neurosci. 2022 Apr 6;21(3):76. doi: 10.31083/j.jin2103076.
Matsunaga S, Kishi T, Nomura I, Sakuma K, Okuya M, Ikuta T, et al. The efficacy and safety of memantine for the treatment of Alzheimer’s disease. Expert Opin Drug Saf. 2018 Oct;17(10):1053-61. doi: 10.1080/14740338.2018.1524870.
Lee DY, Kim EH. Therapeutic Effects of amino acids in liver diseases: current studies and future perspectives. J Cancer Prev. 2019 Jun;24(2):72-8. doi: 10.15430/JCP.2019.24.2.72.
Piubelli L, Murtas G, Rabattoni V, Pollegioni L. The Role of D-Amino acids in Alzheimer’s Disease. J Alzheimers Dis. 2021;80(2):475-92. doi: 10.3233/JAD-201217.
Shen Y, Xia Y, Meng S, Lim NK, Wang W, Huang F. SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer’s Disease. J Alzheimers Dis. 2017;55(2):835-47. doi: 10.3233/JAD-160233.
Sun XY, Li LJ, Dong QX, Zhu J, Huang YR, Hou SJ, et al. Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflammation. 2021 Jun 11;18(1):131. doi: 10.1186/s12974-021-02182-3.
Braidy N, Essa MM, Poljak A, Selvaraju S, Al-Adawi S, Manivasagm T, et al. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer’s disease. Oncotarget. 2016 Oct 4;7(40):64589-604. doi: 10.18632/oncotarget.10905.
Nomura J, Jaaro-Peled H, Lewis E, Nuñez-Abades P, Huppe-Gourgues F, Cash-Padgett T, et al. Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice. Mol Psychiatry. 2016 Mar;21(3):386-93. doi: 10.1038/mp.2015.61.
Sun W, Lin R, Li Y, Yao Y, Lu B, Yu Y. Circulating branched-chain amino acids and the risk of major adverse cardiovascular events in the UK biobank. Front Endocrinol (Lausanne). 2025 Feb 20;16:1510910. doi: 10.3389/fendo.2025.1510910.
Fu Y, Wang Y, Ren H, Guo X, Han L. Branched-chain amino acids and the risks of dementia, Alzheimer’s disease and Parkinson’s disease. Front Aging Neurosci. 2024 Apr 10;16:1369493. doi: 10.3389/fnagi.2024.1369493.
Xiang J, Wang ZH, Ahn EH, Liu X, Yu SP, Manfredsson FP, et al. Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies. Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9094-102. doi: 10.1073/pnas.1901348116.
Hu Z, Ondrejcak T, Yu P, Zhang Y, Yang Y, Klyubin I, et al. Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer’s disease? Neural Regen Res. 2023 Jun;18(6):1213-9. doi: 10.4103/1673-5374.360166.
Abooshahab R, Hooshmand K, Razavi F, Dass CR, Hedayati M. A glance at the actual role of glutamine metabolism in thyroid tumorigenesis. EXCLI J. 2021 Jul 12;20:1170-1183. doi: 10.17179/excli2021-3826.
Zhang D, Hua Z, Li Z. The role of glutamate and glutamine metabolism and related transporters in nerve cells. CNS Neurosci Ther. 2024 Feb;30(2):e14617. doi: 10.1111/cns.14617.
Wang Y, Wang Q, Li J, Lu G, Liu Z. Glutamine Improves Oxidative Stress through the Wnt3a/β-Catenin signaling pathway in alzheimer’s disease in vitro and in vivo. Biomed Res Int. 2019 Apr 16;2019:4690280. doi: 10.1155/2019/4690280.
Huang JL, Zhang F, Su M, Li J, Yi W, Hou LX, et al. MeCP2 prevents age-associated cognitive decline via restoring synaptic plasticity in a senescence-accelerated mouse model. Aging Cell. 2021 Sep;20(9):e13451. doi: 10.1111/acel.13451.
Medd MM, Yon JE, Dong H. RhoA/ROCK/GSK3β Signaling: A keystone in understanding Alzheimer’s Disease. Curr Issues Mol Biol. 2025 Feb 14;47(2):124. doi: 10.3390/cimb47020124.
Saleem S, Shaukat F, Gul A, Arooj M, Malik A. Potential role of amino acids in pathogenesis of schizophrenia. Int J Health Sci (Qassim). 2017 Jul-Sep;11(3):63-8. PMID: 28936154.
Le Douce J, Maugard M, Veran J, Matos M, Jégo P, Vigneron PA, et al. Impairment of glycolysis-derived l-serine production in astrocytes contributes to cognitive deficits in Alzheimer’s disease. Cell Metab. 2020 Mar 3;31(3):503-517.e8. doi: 10.1016/j.cmet.2020.02.004.
Talbert LE, Julian RR. Methionine and selenomethionine as energy transfer acceptors for biomolecular structure elucidation in the gas phase. J Am Soc Mass Spectrom. 2019 Sep;30(9):1601-8. doi: 10.1007/s13361-019-02262-y.
Zhang ZH, Wu QY, Chen C, Zheng R, Chen Y, Ni JZ, et al. Comparison of the effects of selenomethionine and selenium-enriched yeast in the triple-transgenic mouse model of Alzheimer’s disease. Food Funct. 2018 Jul 17;9(7):3965-73. doi: 10.1039/c7fo02063e.
Zheng R, Zhang ZH, Chen C, Chen Y, Jia SZ, Liu Q, et al. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer’s disease. Biochem Biophys Res Commun. 2017 Mar 25;485(1):6-15. doi: 10.1016/j.bbrc.2017.01.069.
Lee YH, Ren D, Jeon B, Liu HW. S-Adenosylmethionine: more than just a methyl donor. Nat Prod Rep. 2023 Sep 20;40(9):1521-49. doi: 10.1039/d2np00086e.
Francioso A, Fanelli S, d’Erme M, Lendaro E, Miraglia N, Fontana M, et al. Pharmacokinetic properties of a novel formulation of S-adenosyl-L-methionine phytate. Amino Acids. 2021 Oct;53(10):1559-68. doi: 10.1007/s00726-021-03076-7.
Li HQ, Ip SP, Yuan QJ, Zheng GQ, Tsim KKW, Dong TTX, et al. Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: Studies in a transgenic mouse model of Alzheimer’s disease. Brain Behav Immun. 2019 Nov;82:264-78. doi: 10.1016/j.bbi.2019.08.194.
Cavallaro RA, Nicolia V, Fiorenza MT, Scarpa S, Fuso A. S-Adenosylmethionine and superoxide dismutase 1 synergistically counteract Alzheimer’s disease features progression in TgCRND8 Mice. Antioxidants (Basel). 2017 Sep 30;6(4):76. doi: 10.3390/antiox6040076.
Emokpae O, Ben-Azu B, Ajayi AM, Umukoro S. D-ribose-L-cysteine enhances memory task, attenuates oxidative stress and acetyl-cholinesterase activity in scopolamine amnesic mice. Drug Dev Res. 2020 Aug;81(5):620-627. doi: 10.1002/ddr.21663.
Ogunlade B, Fidelis OP, Afolayan OO, Agie JA. Neurotherapeutic and antioxidant response of D-ribose-L-Cysteine nutritional dietary supplements on Alzheimer-type hippocampal neurodegeneration induced by cuprizone in adult male wistar rat model. Food Chem Toxicol. 2021 Jan;147:111862. doi: 10.1016/j.fct.2020.111862.
Abdi SAH, Afjal MA, Najmi AK, Raisuddin S. S-allyl cysteine ameliorates cyclophosphamide-induced downregulation of urothelial uroplakin IIIa with a concomitant effect on expression and release of CCL11and TNF-α in mice. Pharmacol Rep. 2018 Aug;70(4):769-76. doi: 10.1016/j.pharep.2018.02.016.
Vicario R, Fragkogianni S, Weber L, Lazarov T, Hu Y, Hayashi SY, et al. A microglia clonal inflammatory disorder in Alzheimer’s disease. Elife. 2025 Mar 14;13. doi: 10.7554/eLife.96519.3.
Tieu S, Charchoglyan A, Paulsen L, Wagter-Lesperance LC, Shandilya UK, Bridle BW, et al. N-Acetylcysteine and its immunomodulatory properties in humans and domesticated animals. Antioxidants (Basel). 2023 Oct 16;12(10):1867. doi: 10.3390/antiox12101867.
Wan C, Xue R, Zhan Y, Wu Y, Li X, Pei F. metabolomic analysis of n-acetylcysteine protection of injury from gadolinium-DTPA contrast agent in rats with chronic renal failure. OMICS. 2017 Sep;21(9):540-9. doi: 10.1089/omi.2017.0114. Epub 2017 Sep 1. PMID: 28934030.
Mozafari N, Shamsizadeh A, Fatemi I, Allahtavakoli M, Moghadam-Ahmadi A, Kaviani E, Kaeidi A. CX691, as an AMPA receptor positive modulator, improves the learning and memory in a rat model of Alzheimer’s disease. Iran J Basic Med Sci. 2018 Jul;21(7):724-30. doi: 10.22038/IJBMS.2018.28544.6934.
Erichsen J, Craft S. Targeting immunometabolic pathways for combination therapy in Alzheimer’s disease. Alzheimers Dement (N Y). 2023 Sep 30;9(4):e12423. doi: 10.1002/trc2.12423.
Amukti DP, Wazni AR, Irham LM, Sulistyani N, Ma’ruf M, Adikusuma W, et al. Identifying pathogenic variants associated with Alzeimer by integrating genomic databases and bioinformatics approaches. InE3S Web of Conferences 2024 (Vol. 501, p. 01021). EDP Sciences.
Zhu G, Yang S, Xie Z, Wan X. Synaptic modification by L-theanine, a natural constituent in green tea, rescues the impairment of hippocampal long-term potentiation and memory in AD mice. Neuropharmacology. 2018 Aug;138:331-40. doi: 10.1016/j.neuropharm.2018.06.030.
Seidel U, Lüersen K, Huebbe P, Rimbach G. Taurine enhances iron-related proteins and reduces lipid peroxidation in differentiated C2C12 Myotubes. Antioxidants (Basel). 2020 Oct 31;9(11):1071. doi: 10.3390/antiox9111071.
Ramezani M, Darbandi N, Khodagholi F, Hashemi A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer’s disease. Neural Regen Res. 2016 Dec;11(12):1976-80. doi: 10.4103/1673-5374.197141.
Velueta-Viveros M, Martínez-Bailén M, Puerta A, Romero-Hernández LL, Křen V, Merino-Montiel P, et al. Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer’s disease. Bioorg Chem. 2022 Oct;127:105983. doi: 10.1016/j.bioorg.2022.105983.
Gu QF, Yu JZ, Wu H, Li YH, Liu CY, Feng L, et al. Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer’s disease. Exp Ther Med. 2018 Nov;16(5):3929-38. doi: 10.3892/etm.2018.6701.
Jorda A, Cauli O, Santonja JM, Aldasoro M, Aldasoro C, Obrador E, et al. Changes in chemokines and chemokine receptors expression in a mouse model of Alzheimer’s disease. Int J Biol Sci. 2019 Jan 1;15(2):453-63. doi: 10.7150/ijbs.26703.
Isaković J, Gorup D, Mitrečić D. Molecular mechanisms of microglia- and astrocyte-driven neurorestoration triggered by application of electromagnetic fields. Croat Med J. 2019 Apr 30;60(2):127-40. doi: 10.3325/cmj.2019.60.127.
Djuric D, Jakovljevic V, Zivkovic V, Srejovic I. Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol. 2018 Oct;96(10):991-1003. doi: 10.1139/cjpp-2018-0112.
Pierozan P, Biasibetti-Brendler H, Schmitz F, Ferreira F, Netto CA, Wyse ATS. Synergistic toxicity of the neurometabolites quinolinic acid and homocysteine in cortical neurons and astrocytes: implications in Alzheimer’s disease. Neurotox Res. 2018 Jul;34(1):147-63. doi: 10.1007/s12640-017-9834-6.
Maneechote C, Palee S, Kerdphoo S, Jaiwongkam T, Chattipakorn SC, Chattipakorn N. Pharmacological inhibition of mitochondrial fission attenuates cardiac ischemia-reperfusion injury in pre-diabetic rats. Biochem Pharmacol. 2020 Dec;182:114295. doi: 10.1016/j.bcp.2020.114295.
Wang Y, Yu Y, Wang Q, Wei S, Wang S, Qin Q, et al. PPAR-δ of orange-spotted grouper exerts antiviral activity against fish virus and regulates interferon signaling and inflammatory factors. Fish Shellfish Immunol. 2019 Nov;94:38-49. doi: 10.1016/j.fsi.2019.08.068.
Popova AA, Koksharova OA. Neurotoxic Non-proteinogenic amino acid β-N-Methylamino-L-alanine and Its role in biological systems. Biochemistry (Mosc). 2016 Aug;81(8):794-805. doi: 10.1134/S0006297916080022.
Downing S, Downing TG. The metabolism of the non-proteinogenic amino acid β-N-methylamino-L-alanine (BMAA) in the cyanobacterium Synechocystis PCC6803. Toxicon. 2016 Jun 1;115:41-8. doi: 10.1016/j.toxicon.2016.03.005.
Silva DF, Candeias E, Esteves AR, Magalhães JD, Ferreira IL, Nunes-Costa D, et al. Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation and Alzheimer’s disease features in cortical neurons. J Neuroinflammation. 2020 Nov 5;17(1):332. doi: 10.1186/s12974-020-02004-y.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
