State-of-the-Art Technologies for Studying Cellular and Molecular Mechanisms Underlying Alzheimer's Disease

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Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and cause of dementia. It is associated with progressive cognitive decline due to the development of cortical and hippocampal atrophy.

We reviewed key factors in AD pathogenesis, such as synaptic dysfunction, accumulation and aggregation of amyloid beta (Aβ) peptide, tau phosphorylation causing neurofibrillary tangles, mitochondrial dysfunction, and neuroinflammation. We studied the dysbiosis role in AD development and demonstrated how much the bidirectional communication between the gut and brain sheds new light on some pathogenic processes underlying AD. We reviewed state-of-the-art biomedical technologies for studying AD: transgenic models, electrophysiological techniques, optogenetics, multi-omics approaches, neuroimaging, etc. New biomedical technologies significantly expanded our current knowledge of the AD pathogenesis and laid the groundwork for state-of-the-art treatment approaches.

About the authors

Marat A. Mukhamedyarov

Kazan State Medical University

Author for correspondence.
Email: marat.muhamedyarov@kazangmu.ru
ORCID iD: 0000-0002-0397-9002

D. Sci. (Med.), Professor, Head, Department of normal physiology

Russian Federation, Kazan

Liaisan A. Akhmadieva

Kazan State Medical University

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0009-0000-4926-3192

student, General medicine faculty

Russian Federation, Kazan

Kerim K. Nagiev

Kazan State Medical University

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0009-0000-1577-9780

postgraduate student, Department of the normal physiology

Russian Federation, Kazan

Andrey L. Zefirov

Kazan State Medical University

Email: annaly-nevrologii@neurology.ru
ORCID iD: 0000-0001-7436-7815

D. Sci. (Med.), Academician of RAS, Professor, Department of normal physiology

Russian Federation, Kazan

References

  1. Naseri N., Wang H., Guo J. et al. The complexity of tau in Alzheimer’s disease. Neurosci. Lett. 2019;705:183–194. doi: 10.1016/j.neulet.2019.04.022
  2. Patterson C. World Alzheimer report 2018. The State of the art of dementia research: new frontiers. London; 2018; 48 p.
  3. Ghavami S., Shojaei S., Yeganeh B. et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog. Neurobiol. 2014;112:24–49. doi: 10.1016/j.pneurobio.2013.10.004
  4. Eshraghi M., Adlimoghaddam A., Mahmoodzadeh A. et al. Alzheimer’s disease pathogenesis: role of autophagy and mitophagy focusing in microglia. Int. J. Mol. Sci. 2021;22(7):3330. doi: 10.3390/ijms22073330
  5. Laurent C., Buée L., Blum D. Tau and neuroinflammation: what impact for Alzheimer’s disease and tauopathies? Biomed. J. 2018;41(1):21–33. doi: 10.1016/j.bj.2018.01.003
  6. Vidal C., Zhang L. An analysis of the neurological and molecular alterations underlying the pathogenesis of Alzheimer’s disease и Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Cells. 2021;10(3):546. doi: 10.3390/cells10030546
  7. Tiwari S., Atluri V., Kaushik A. et al. Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int. J. Nanomedicine. 2019;14:5541–5554. doi: 10.2147/IJN.S200490
  8. Xia X., Jiang Q., McDermott J., Jing-Dong J. Aging and Alzheimer’s disease: comparison and associations from molecular to system level. Aging Cell. 2018;17(5):e12802. doi: 10.1111/acel.12802
  9. Faux N.G., Rembach A., Wiley J. et al. An anemia of Alzheimer’s disease. Mol. Psychiatry. 2014;19(11):1227–1234. doi: 10.1038/mp.2013.178
  10. Татарникова О.Г., Орлов М.А., Бобкова Н.В. Бета-амилоид и тау-белок: структура, взаимодействие и прионоподобные свойства. Успехи биологической химии. 2015;55:351–390. Tatarnikova O.G., Orlov M.A., Bobkova N.V. Beta-amyloid and tau-protein: structure, interaction, and prion-like properties. Biochemistry (Mosc.). 2015;80(13):1800–1819. (In Russ.). doi: 10.1134/S000629791513012X
  11. Мухамедьяров М.А., Зефиров А.Л. Влияние β-амилоидного пептида на функции возбудимых тканей: физиологические и патологические аспекты. Успехи физиологических наук. 2013;44(1):55–71. Muhamedjarov M.A., Zefirov A.L. Influence of β-amyloid peptide on functions of excitable tissues: physiological and pathological aspects. Advances in physiologi- cal sciences. 2013;44(1):55–71. (In Russ.)
  12. Huang Y., Liu R. The toxicity and polymorphism of β-amyloid oligomers. Int. J. Mol. Sci. 2020; 21(12):4477. doi: 10.3390/ijms21124477
  13. d‘Errico P., Meyer-Luehmann M. Mechanisms of pathogenic tau and Aβ protein spreading in Alzheimer’s disease. Front. Aging Neurosci. 2020;12:265. doi: 10.3389/fnagi.2020.00265
  14. Eshraghi M., Adlimoghaddam A., Mahmoodzadeh A. et al. Alzheimer’s disease pathogenesis: role of autophagy and mitophagy focusing in microglia. Int. J. Mol. Sci. 2021;22(7):3330. doi: 10.3390/ijms22073330
  15. Arnsten A., Datta D., Tredici K., Braak H. Hypothesis: tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimer’s Dement. 2021;17:115–124. doi: 10.1002/alz.12192
  16. Chen J.X., Yan S.D. Amyloid-β-induced mitochondrial dysfunction. J. Alzheimers Dis. 2007;12(2):177–184.
  17. Chen G., Xu T., Yan Y. et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017;38(9):1205–1235. doi: 10.1038/aps.2017.28
  18. Perez Ortiz J.M., Swerdlow R.H. Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br. J. Pharmacol. 2019;176(18):3489–3507. doi: 10.1111/bph.14585
  19. Левченкова О.С., Новиков В.Е., Пожилова Е.В. Митохондриальная пора как мишень фармакологического воздействия. Вестник Смоленской государственной медицинской академии. 2014;13(4):24–33. Levchenkova O.S., Novikov V.E., Pozhilova E.V. Mitochondrial pore as a target for pharmacological exposure. Vestnik of Smolensk State Medical Academy. 2014;13(4):24–33. (In Russ.)
  20. Glick D., Barth S., Macleod K.F. Autophagy: cellular and molecular mechanisms. J. Pathol. 2010;221(1):3–12. doi: 10.1002/path.2697
  21. Ghavami S., Shojaei S., Yeganeh B. et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog. Neurobiol. 2014;112:24–49. doi: 10.1016/j.pneurobio.2013.10.004
  22. Hansen D.V., Hanson J.E., Sheng M. Microglia in Alzheimer’s disease. J. Cell Biol. 2018;217(2):459–472. doi: 10.1083/jcb.201709069
  23. Guo S., Wang H., Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front. Aging Neurosci. 2022;14:815347. doi: 10.3389/fnagi.2022.815347
  24. Chew G., Petretto E. Transcriptional networks of microglia in Alzheimer’s disease and insights into pathogenesis. Genes (Basel). 2019;10(10):798. doi: 10.3390/genes10100798
  25. Harry G.J. Microglia during development and aging. Pharmacol. Ther. 2013;139(3):313–326. doi: 10.1016/j.pharmthera.2013.04.013
  26. Borst K., Dumas A.A., Prinz M. Microglia: immune and non-immune functions. Immunity. 2021;54(10):2194–2208. doi: 10.1016/j.immuni.2021.09.014
  27. Soteros B.M., Sia G.M. Complement and microglia dependent synapse elimination in brain development. WIREs Mech. Dis. 2022;14(3):e1545. doi: 10.1002/wsbm.1545
  28. Горбачёва Л.Р., Помыткин И.А., Сурин А.М. и др. Астроциты и их роль в патологии центральной нервной системы. Российский педиатрический журнал. 2018;21(1):46–53. Gorbacheva L.R., Pomytkin L.A., Surin A.M. et al. Astrocytes and their role in the pathology of the central nervous system. The Russian Pediatric Journal. 2018;21(1):46–53. (In Russ.)
  29. Liddelow S.A., Guttenplan K.A., Clarke L.E. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–487. doi: 10.1038/nature21029
  30. Cascella R., Cecchi C. Calcium dyshomeostasis in Alzheimer’s disease pathogenesis. Int. J. Mol. Sci. 2021;22(9):4914. doi: 10.3390/ijms22094914
  31. Wang X., Zheng W. Ca2+ homeostasis dysregulation in Alzheimer’s disease: a focus on plasma membrane and cell organelles. FASEB J. 2019;33(6):6697–6712. doi: 10.1096/fj.201801751R
  32. Wang W., Zhao F., Ma X. et al. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol. Neurodegener. 2020;15(1):30. doi: 10.1186/s13024-020-00376-6
  33. Sochocka M., Donskow-Łysoniewska K., Diniz B.S. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease — a critical review. Mol. Neurobiol. 2019;56(3):1841–1851. doi: 10.1007/s12035-018-1188-4
  34. Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018;1693(Pt B):128–133. doi: 10.1016/j.brainres.2018.03.015
  35. Megur А., Baltriukienė D., Bukelskienė V. The microbiota–gut–brain axis and Alzheimer’s disease: neuroinflammation is to blame? Nutrients. 2020;24;13(1):37. doi: 10.3390/nu13010037
  36. Sun Y., Sommerville N.R., Liu J. Intra – gastrointestinal amyloid – β1–42 oligomers perturb enteric function and induce Alzheimer’s disease pathology. J. Physiol. 2020;598(19):4209–4223. doi: 10.1113/JP279919
  37. Friedland R.P., Chapman M.R. The role of microbial amyloid in neurodegene- ration. PLoS Pathog. 2017;13(12):e1006654. doi: 10.1371/journal.ppat.1006654
  38. Tai L.M., Weng J.M., LaDu M.J., Brady S.T. Relevance of transgenic mouse models for Alzheimer’s disease. Prog. Mol. Biol. Transl. Sci. 2021;177:1–48. doi: 10.1016/bs.pmbts.2020.07.007
  39. Nakai T., Yamada K., Mizoguchi H. Alzheimer’s disease animal models: elucidation of biomarkers and therapeutic approaches for cognitive impairment. Int. J. Mol. Sci. 2021;22(11):5549. doi: 10.3390/ijms22115549
  40. Wirths O., Zampar S. Neuron loss in Alzheimer’s Disease: translation in transgenic mouse models. Int. J. Mol. Sci. 2020;21(21):8144. doi: 10.3390/ijms21218144
  41. Tönnies E., Trushina E. Oxidative Stress, synaptic dysfunction, and Alzheimer’s disease. J. Alzheimers Dis. 2017;57(4):1105–1121. doi: 10.3233/JAD-161088
  42. Babiloni C., Blinowska K., Bonanni L. et al. What electrophysiology tells us about Alzheimer’s disease: a window into the synchronization and connectivity of brain neurons. Neurobiol. Aging. 2020;85:58–73. doi: 10.1016/j.neurobiolaging.2019.09.008
  43. Шуваев А.Н., Салмин В.В., Кувачева Н.В. и др. Современные тенденции в развитии метода локальной фиксации потенциала: новые возможности для нейрофармакологии и нейробиологии. Анналы клинической и экспериментальной неврологии. 2015;9(4):54–58. Shuvaev A.N., Salmin V.V., Kuvacheva N.V. et al. Modern tendencies in the development of the patch-clamp technique: new opportunities for neuropharmacology and neurobiology. Annals of clinical and experimental neurology. 2015;9(4):54–58. (In Russ.)
  44. Новиков Н.И., Бражник Е.С., Кичигина В.Ф. Применение опто- и хемогенетических методов для изучения двигательных нарушений при болезни Паркинсона. Современные технологии в медицине. 2019;11(2):150–163. Novikov N.I., Brazhnik E.S., Kichigina V.F. The use of optogenetic and dreadds techniques: applications to the behavioral pathology in Parkinson’s disease. Sovremennye tehnologii v medicine. 2019;11(2):150–163. (In Russ.). doi: 10.17691/stm2019.11.2.21
  45. Mirzayi P., Shobeiri P., Kalantari A. et al. Optogenetics: implications for Alzheimer’s disease research and therapy. Mol. Brain. 2022;15(1):20. doi: 10.1186/s13041-022-00905-y
  46. Lim C.H., Kaur P., Teo E. et al. Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration. Elife. 2020;9:e52589. doi: 10.7554/eLife.52589
  47. Власова О.Л., Артамонов Д.Н., Ерофеев А.И., Безпрозванный И.Б. Применение оптогенетических подходов к исследованию электрофизиологических особенностей нейронов у мышей-моделей нейродегенеративных заболеваний. Первая Всероссийская конференция и Школа с международным участием «Оптогенетика и оптофармакология»: cборник научных трудов. СПб.; 2018:23–25. Vlasova O.L., Artamonov D.N., Erofeev A.I. Application of optogenetic approaches to the study of electrophysiological features of neurons in mouse mo-dels of neurodegenerative diseases. In: First All-Russian Conference and School with International Participation “Optogenetics and Optopharmacology”: collection of scientific papers. St. Petersburg; 2018:23–25. (In Russ.)
  48. Ying Y., Wang J. Illuminating neural circuits in Alzheimer’s disease. Neuro- sci. Bull. 2021;37(8):1203–1217. doi: 10.1007/s12264-021-00716-6
  49. Rayaprolu S., Higginbotham L., Bagchi P. et al. Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau. Neuropsychopharmacology. 2021;46(1):98–115. doi: 10.1038/s41386-020-00840-3
  50. Jung T.J., Kim Y.H., Bhalla M. et al. Genomics: new light on Alzheimer’s disease research. Int. J. Mol. Sci. 2018;19(12):3771. doi: 10.3390/ijms19123771
  51. Bertram L., Tanzi R.E. Genomic mechanisms in Alzheimer’s disease. Brain Pathol. 2020;30(5):966–977. doi: 10.1111/bpa.12882
  52. Mathys H., Davila-Velderrain J., Peng Z. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570(7761):332–337. doi: 10.1038/s41586-019-1195-2.
  53. Muñoz-Castro C., Noori A., Magdamo C.J. et al. Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimer’s disease. J. Neuroinflammation. 2022;19(1):30. doi: 10.1186/s12974-022-02383-4
  54. Vinters H.V. Emerging concepts in Alzheimer’s disease. Annu. Rev. Pathol. Mech. Dis. 2015;10:291–319. doi: 10.1146/annurev-pathol-020712-163927
  55. Reitz C., Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 2014;88(4):640–651. doi: h10.1016/j.bcp.2013.12.024
  56. Qiu S., Joshi P.S., Miller M.I. et al. Development and validation of an interpretable deep learning framework for Alzheimer’s disease classification. Brain. 2020;143(6):1920–1933. doi: 10.1093/brain/awaa137

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2. Fig. 1. Cellular and molecular mechanisms underlying AD.

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3. Fig. 2. Interaction between the brain and the gut microbiota in AD. The gut microbiota–brain axis involves various communication routes between the gut and the brain that can operate together or independently. Metabolites, lipopolysaccharides, and bacterial amyloids produced by the gut microbiota can influence the brain functioning. In case of dysbiosis, such communication routes as autonomic nervous system, neuroendocrine system, metabolic pathway, and immune system trigger the brain neuroinflammation leading to AD onset and progression.

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Copyright (c) 2023 Mukhamedyarov M.A., Akhmadieva L.A., Nagiev K.K., Zefirov A.L.

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