This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (CC BY).
ORIGINAL RESEARCH
Optimal HAEE synthetic peptide therapeutic dose with repeated administration to APP/PS1 mice
1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
2 Pirogov Russian National Research Medical University, Moscow, Russia
3 Scientific Centre RTA LLC, Moscow, Russia
Correspondence should be addressed: Vladimir A. Mitkevich
Vavilova, 32, Moscow, 119991; ur.bmie@hcivektim
Funding: the study was supported by the Ministry of Health of the Russian Federation, topic: Pharmaceutical Development and Preclinical Trials of the Peptide Drug for Treatment of Alzheimer's Disease, 125022602911-9.
Acknowledgements: the authors would like to express their gratitude to E.V. Myachin, Chairman of the VSE Cooperative (Moscow, Russia), for providing the HAEE lyophilized synthetic peptide.
Author contribution: Kozin SA — study design, literature review, manuscript writing; Lysikova EA — experimental research involving APP/PS1 mice, проведение transcardial perfusion, histochemical analysis; Yakovlev RYu — analysis of the input HAEE synthetic peptide samples; Mukhina KA, Soloveva АЕ, Shmigol TA — experimental research involving APP/PS1 mice, preparation of brain slices, fluorescence microscopy image acquisition and analysis; Makarov AA, Mitkevich VA — study design, manuscript writing.
Compliance with ethical standards: the study was approved by the Ethics Committee of the Engelhardt Institute of Molecular Biology RAS (protocol No. 3 dated 11 September 2025) and conducted in accordance with guidelines for working with laboratory animals.
- Livingston G, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020; 396 (10248): 413–46.
- Mihajlova NM. Organizaciya vnebol'nichnoj gerontopsihiatricheskoj pomoshchi pri demencii i kognitivnom snizhenii. CHast' 1: Demograficheskie sdvigi, sozdanie kliniki pamyati i Al'cgejmerovskih centrov. ZHurnal nevrologii i psihiatrii im. S. S. Korsakova. 2017; 117 (6): 111–19. Russian.
- Jagust W, et al. “Alzheimer's disease” is neither “Alzheimer's clinical syndrome” nor “dementia”. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 2019; 15 (1): 153–7.
- Hampel H, et al. The Amyloid-β Pathway in Alzheimer’s Disease. Molecular Psychiatry. 2021; 26 (10): 5481–03.
- Roher AE, et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease. Alzheimers Dement. 2009; 5 (1): 18–29.
- Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019; 179 (2): 312–39.
- Cummings JL, et al. Alzheimer's disease drug development pipeline: 2025. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2025; 11 (2): e70098.
- Budd Haeberlein S, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer's Disease. 2022; 9 (2): 197–210.
- Mintun MA, et al. Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021; 384 (18): 1691–704.
- van Dyck CH, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023; 388 (1): 9–21.
- Hardy J, Mummery C. An anti-amyloid therapy works for Alzheimer’s disease: why has it taken so long and what is next? Brain. 2023; 146 (4): 1240–2.
- Kepp KP, et al. The amyloid cascade hypothesis: an updated critical review. Brain. 2023; 146 (10): 3969–90.
- Wang C, et al. Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide. International Journal of Molecular Sciences. 2023; 24 (17): 13110.
- Kozin SA, i dr. Peptid Ac-His-Ala-Glu-Glu-NH2 i ego proizvodnye, prednaznachennye dlya vosstanovleniya deficita endogennogo komponenta krovi cheloveka. Patent RF №2826728. Oficial'nyj byulleten' Federal'noj sluzhby po intellektual'noj sobstvennosti (Rospatent) №26–2024, 11/09/2024-20/09/2024, 2024. Russian.
- Ivanova AV, et al. Comparative pharmacokinetics and biodistribution of HAEE and HASS peptides. Bulletin of RSMU. 2025 (4): 45–50.
- Kozin SA. Rol' vzaimodejstvij cinka i beta-amiloida v patogeneze bolezni Al'cgejmera. Uspekhi biologicheskoj himii. 2023; 63: 149–74. Russian.
- Nikolskij KS, i dr. Issledovanie interfejsa svyazyvaniya beta-amiloida s kandidatnym markerom nejrodegenerativnyh zabolevanij. Matematicheskaya biologiya i bioinformatika. 2025; 20 (1): 212–35. Russian.
- Kozin SA, et al. Switching On/Off Amyloid Plaque Formation in Transgenic Animal Models of Alzheimer’s Disease. International Journal of Molecular Sciences. 2024; 25 (1): 72.
- Lysikova EA, i dr. Liniya transgennyh myshej APPswe/PS1dE9/Blg dlya modelirovaniya cerebral'nogo amiloidoza pri bolezni Al'cgejmera. Molekulyarnaya biologiya. 2023; 57 (1): 85–94. Russian.
- Jankowsky JL, et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001; 17 (6): 157–65.
- Rybakova AV, i dr. Sushchestvuyushchie trebovaniya i podhody k dozirovaniyu lekarstvennyh sredstv laboratornym zhivotnym. Vedomosti Nauchnogo centra ekspertizy sredstv medicinskogo primeneniya. 2018; 8 (4): 207–17. Russian.
- Paxinos G, Franklin KBJ. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates. 4th ed. Elsevier Academic Press, 2013.
- Garcia-Alloza M, et al., Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiology of Disease. 2006; 24 (3): 516–24.
- Tsvetkov PO, et al. Peripherally Applied Synthetic Tetrapeptides HAEE and RADD Slow Down the Development of Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice. J Alzheimers Dis. 2015; 46 (4): 849–53.
- Kozin SA. Cinkovyj kompleks peptida HAEE dlya lecheniya nejrodegenerativnyh zabolevanij. Patent RF №2784319. Oficial'nyj byulleten' Federal'noj sluzhby po intellektual'noj sobstvennosti (Rospatent), № 33–2022, 21/11/2022-27/11/2022, 2022. Russian.
- Patrakhanov E. Effectiveness of the tetrapeptide HAEE: an innovative approach to Alzheimer’s treatment in experimentation. Research Results in Pharmacology. 2024; 10 (4): 107–11.
- Kuzubova E, et al. Sex-Dependent Phenotypic and Histomorphometric Biomarkers in the APPswe/PS1dE9/Blg Mouse Model of Alzheimer’s Disease. Brain Sciences. 2025; 15 (11): 1237.
- Meyer-Luehmann M, et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008; 451 (7179): 720–4.
- Nirmalraj PN, Bhattacharya S, Thompson D. Accelerated Alzheimer’s Aβ-42 secondary nucleation chronologically visualized on fibril surfaces. Science Advances. 2024; 10 (43): eadp5059.
- Mukhina KA, et al. The Tetrapeptide HAEE Promotes Amyloid-Beta Clearance from the Brain. International Journal of Molecular Sciences. 2025; 26 (23): 11591.