Mitochondrial cascade in the sporadic form of Alzheimer’s disease in an experiment

Original article

УДК 001.891+576.311.347
DOI: 10.29296/2618723X-2022-02-06

D.I. Pozdnyakov, Associate Professor of the Department of Pharmacology with a Course in Clinical Pharmacology,

Pyatigorsk Medical and Pharmaceutical Institute, branch of Volgograd State Medical University,
357532, Russia, Stavropol Territory, Pyatigorsk, Kalinina Ave., 11

e-mail: [email protected]

Keywords: mitochondrial cascade mitochondrial dysfunction neurodegenerative diseases Alzheimer’s disease

For citation:

Pozdnyakov D. I. Mitochondrial cascade in the sporadic form of Alzheimer’s disease in an experiment. Laboratory Animals for Science. 2022; 2.


Pathophysiological reactions of the «mitotondrial cascade» are an important component of the pathogenesis of neurodegenerative diseases, in particular Alzheimer’s disease, and can serve as a basis for neuroprotective intervention, which suggests the relevance of their study.

The aim of the study. To evaluate the dependence of changes in mitochondrial function parameters on changes in tau protein content in the hippocampus of rats in experimental Alzheimer’s disease of sporadic type.

Material and methods. Alzheimer’s disease was modeled in Wistar rats by injection of Aβ1–42 fragments into the CA1 part of the hippocampus. After 60 days of exposure, the development of cognitive deficits in rats was assessed in the Y-shaped maze test. Cognitive deficits in animals were assessed by changes in the number of spontaneous alternations of maze arms Changes of the ATP concentration, tau protein, mitochondrial hydrogen peroxide and the activity of enzymes: aconitase, citrate synthase, cytochrome c oxidase, succinate dehydrogenase were evaluated in the hippocampus of animals. The change in the value of the mitochondrial membrane potential was also evaluated. The content of ATP and tau protein was determined by enzyme immunoassay. The activity of mitochondrial enzymes was evaluated spectrometrically when the corresponding substrates were introduced into the reaction medium. The concentration of mitochondrial hydrogen peroxide was determined by a change in the fluorescence of resorufin. The membrane potential of mitochondria was evaluated by spectrophotometric method. The data was processed statistically. During the analysis, the Spearman correlation coefficient was calculated.

Results. The study found that in rats with Alzheimer’s disease, compared with sham-operated animals, there was a decrease in the activity of citrate synthase, aconitase, cytochrome c oxidase, succinate dehydrogenase, mitochondrial membrane potential and ATP concentration with an increase in the content of mitochondrial hydrogen peroxide and tau protein. Also, in rats with experimental pathology, the development of a pronounced cognitive deficit was observed, which directly correlated with a change in the concentration of tau protein (r=0.9950). In turn, changes of tau protein content correlated with changes of citrate synthase activity (r=0.95806) and ATP concentration (r=0.9798). The obtained data may indicate that the accumulation of phosphorylated tau protein aggregates in brain tissue in Alzheimer’s disease may depend from mitochondrial biogenesis (citrate synthase activity) and the integral activity of the cell mitochondria (ATP concentration).


  1. Scheltens P., De Strooper B., Kivipelto M. et al. Alzheimer’s disease // Lancet. 2021. Vol. 397. N. 10284. P. 1577–1590. DOI:10.1016/s0140-6736(20)32205-4.
  2. Lei P., Ayton S., Bush A. I. The essential elements of Alzheimer’s disease // J. Biol. Chem. 2021. Vol. 296. P. 100105. DOI: 10.1074/jbc.REV120.008207.
  3. Swerdlow R. H. Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease // J. Alzheimers Dis. 2018. Vol. 62. N. 3. P. 1403–1416. DOI: 10.3233/JAD-170585.
  4. Rice A. M., Rosen M. K. ATP controls the crowd // Science. 2017. Vol. 356. N. 6339. P. 701–702. DOI: 10.1126/science.aan4223.
  5. Esquerda-Canals G., Montoliu-Gaya L., Güell-Bosch J., Villegas S. Mouse Models of Alzheimer’s Disease // J. Alzheimers Dis. 2017. Vol. 57. N. 4. P. 1171–1183. DOI: 10.3233/JAD-170045.
  6. Percie du Sert N., Hurst V., Ahluwalia A. et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research // PLoS Biol. 2020. Vol. 18. N. 7. P. e3000410. DOI: 10.1371/journal.pbio.3000410.
  7. Manczak M., Reddy P. H. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage // Hum. Mol. Genet. 2012. Vol. 21. N. 11. P. 2538–2547. DOI: 10.1093/hmg/dds072.
  8. Amani M., Zolghadrnasab M., Salari A. A. NMDA receptor in the hippocampus alters neurobehavioral phenotypes through inflammatory cytokines in rats with sporadic Alzheimer-like disease // Physiol. Behav. 2019. Vol. 202. P. 52–61. DOI: 10.1016/j.physbeh.2019.01.005.
  9. Connolly N. MC, Theurey P., Adam-Vizi V. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases // Cell Death Differ. 2018. Vol. 25. N. 3. P. 542–572. DOI: 10.1038/s41418‑017‑0020‑4.
  10. Ternette N., Yang M., Laroyia M. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency // Cell Rep. 2013. Vol. 3. N. 3. P. 689–700. DOI: 10.1016/j.celrep.2013.02.013.
  11. Shepherd D., Garland P. B. The kinetic properties of citrate synthase from rat liver mitochondria // Biochem. J. 1969. Vol. 114. N. 3. P. 597–610. DOI: 10.1042/bj1140597.
  12. Li Y., D’Aurelio M., Deng J. H. An assembled complex IV maintains the stability and activity of complex I in mammalian mitochondria // J. Biol. Chem. 2007. Vol. 282. N. 24. P. 17557–17562. DOI: 10.1074/jbc.M701056200.
  13. Wang H., Huwaimel B., Verma K. Synthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5 // ChemMedChem. 2017. Vol. 12. N. 13. P. 1033–1044. DOI: 10.1002/cmdc.201700196.
  14. Zhyliuk V. I., Mamchur V. V., Pavlov S. Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia // Eksp. i klin. farm. 2015. Vol. 78. P. 4–10.
  15. Akoglu H. User’s guide to correlation coefficients // Turk J. Emerg. Med. 2018. Vol. 18. N. 3. P. 91–93. DOI: 10.1016/j.tjem.2018.08.001.
  16. Pereira J. B., Janelidze S., Ossenkoppele R. et al. Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease // Brain. 2021. Vol. 144. N. 1. P. 310–324. DOI: 10.1093/brain/awaa395.
  17. Molnar M. J., Kovacs G. G. Mitochondrial diseases // Handb Clin. Neurol. 2017. Vol. 145. P. 147–155. DOI: 10.1016/B978‑0‑12‑802395‑2.00010-9.
  18. Ranjbarvaziri S., Kooiker K. B., Ellenberger M. et al. Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy // Circulation. 2021. Vol. 144. N. 21. P. 1714–1731. DOI: 10.1161/CIRCULATIONAHA.121.053575

Received: 2022-02-10
Reviewed: 2022-06-03
Accepted for publication: 2022-06-13

You may be interested