Enhanced cognitive protection through the combination of Amylovis-201,an anti-amyloidogenic agent with sigma-1 receptor agonist activity,and environmental enrichment in mice
Restricted accessResearch articleFirst published online 2026
Enhanced cognitive protection through the combination of Amylovis-201,an anti-amyloidogenic agent with sigma-1 receptor agonist activity,and environmental enrichment in mice
Amylovis-201 (CNEURO-201) shows strong neuroprotective activity in Alzheimer’s disease (AD) models due to its anti-Aβ aggregating properties and sigma-1 receptors (S1R) agonist activity. The drug is neuroprotective in transgenic rodent models of AD that could translate into disease-modifying effects by both protecting neuronal and glial viability and actively decreasing amyloid aggregation. The individual vulnerability to the neurodegenerative process in AD is highly dependent on the “cognitive reserve,” understood as the efficacy of brain plasticity throughout lifetime events.
Aims:
We aimed to determine whether Amylovis-201 efficacy in AD could be potentiated through stimulation of cognitive reserve. We combined Amylovis-201 administration with an experimental model of environmental enrichment (EE), using training on the Hamlet device. We analyzed the potentiating effects of the combination on brain plasticity and the development of resilience against memory deficits in a pharmacological AD model.
Methods:
We implemented a combined protocol with repeated per os (PO) administration of Amylovis-201 (0.1 and 1 mg/kg) and EE over 2 weeks (5 days/week), consisting of a 4-hour exploration of the Hamlet, a complex environment mimicking a small village with five functionalized houses.
Results:
The combination of EE and low dose (0.1 mg/kg PO) of Amylovis-201 had an additive effect on hippocampal neurogenesis. It also protected mice against scopolamine (0.5 mg/kg IP)-induced spatial working memory deficits in the Y-maze and, at 0.1 or 1 mg/kg PO, against Aβ25–35-induced memory deficits.
Conclusion:
As EE is known to increase S1R expression, the combination of EE and Amylovis-201 had major effects on brain plasticity and neuroprotection.
AlonsoGPhanVGuillemainI, et al. (2000) Immunocytochemical localization of the sigma1 receptor in the adult rat central nervous system. Neuroscience97(1): 155–170. https://doi.org/10.1016/s0306-4522(00)00014-2
2.
AraiJAFeigLA (2011) Long-lasting and transgenerational effects of an environmental enrichment on memory formation. Brain Research Bulletin85(1–2): 30–35. https://doi.org/10.1016/j.brainresbull.2010.11.003
3.
ArendashGWGarciaMFCostaDA, et al. (2004) Environmental enrichment improves cognition in aged Alzheimer’s transgenic mice despite stable b-amyloid deposition. Neuroreport15(11): 1751–1754. https://doi.org/10.1097/01.wnr.0000137183.68847.4e
4.
BranchiIFranciaNAllevaE (2004) Epigenetic control of neurobehavioural plasticity: The role of neurotrophins. Behavioural Pharmacology15(5–6): 353–362. https://doi.org/10.1097/00008877-200409000-00006
5.
CanetGZussyCHernandezC, et al. (2023) The pathomimetic oAβ25–35 model of Alzheimer’s disease: Potential for screening of new therapeutic agents. Pharmacology & Therapeutics245: 108398. https://doi.org/10.1016/j.pharmthera.2023.108398
6.
CarlesAFreyssinAGuehairiaS, et al. (2025) Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer’s disease. Alzheimer’s Research & Therapy17(1): 7. https://doi.org/10.1186/s13195-024-01648-9
7.
ChumakovINabirotchkinSCholetN, et al. (2015) Combining two repurposed drugs as a promising approach for Alzheimer’s disease therapy. Scientific Reports5: 7608. https://doi.org/10.1038/srep07608
8.
CrouzierLMauriceT (2018) Assessment of topographic memory in mice in a complex environment using the Hamlet test. Current Protocols in Mouse Biology8(2): e43. https://doi.org/10.1002/cpmo.43
9.
CrouzierLGilabertDRosselM, et al. (2018) Topographical memory analyzed in mice using the Hamlet Test, a novel complex maze. Neurobiology of Learning and Memory149: 118–134. https://doi.org/10.1016/j.nlm.2018.02.014
10.
CrouzierLCoulySRoquesC, et al. (2020) Sigma-1 (σ1) receptor activity is necessary for physiological brain plasticity in mice. European Neuropsychopharmacology39: 29–45. https://doi.org/10.1016/j.euroneuro.2020.08.010
11.
DuringMJCaoL (2006) VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Current Alzheimer Research3(1): 29–33. https://doi.org/10.2174/156720506775697133
12.
Estévez-SilvaHMCuestoGRomeroN, et al. (2022) Pridopidine promotes synaptogenesis and reduces spatial memory deficits in the Alzheimer’s disease APP/PS1 mouse model. Neurotherapeutics19(5): 1566–1587. https://doi.org/10.1007/s13311-022-01280-1
13.
FisherABezprozvannyIWuL, et al. (2016) AF710B, a novel M1/σ1 agonist with therapeutic efficacy in animal models of Alzheimer’s disease. Neurodegenerative Diseases16(1–2): 95–110. https://doi.org/10.1159/000440864
García-PupoLCrouzierLBencomo-MartínezA, et al. (2024) Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein. Acta Pharmaceutica Sinica B14(10): 4345–4359. https://doi.org/10.1016/j.apsb.2024.06.013
16.
HaleyTJMcCormickWG (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. British Journal of Pharmacology12(1): 12–15. https://doi.org/10.1111/j.1476-5381.1957.tb01354.x
17.
HallHIulitaMFGubertP, et al. (2018) AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer’s disease. Alzheimer’s & Dementia14(6): 811–823. https://doi.org/10.1016/j.jalz.2017.11.009
18.
HampelHWilliamsCEtchetoA, et al. (2020) A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement (NY)6(1): e12013. https://doi.org/10.1002/trc2.12013
19.
HayashiTSuTP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell131(3): 596–610. https://doi.org/10.1016/j.cell.2007.08.036
20.
HayashiTMauriceTSuTP (2000) Ca2+ signaling via sigma1-receptors: Novel regulatory mechanism affecting intracellular Ca2+ concentration. Journal of Pharmacology and Experimental Therapeutics293(3): 788–798. https://doi.org/10.1016/S0022-3565(24)39299-7
21.
HungASLiangYChowTC, et al. (2016) Mutated tau, amyloid and neuroinflammation in Alzheimer disease-A brief review. Progress in Histochemistry and Cytochemistry51(1): 1–8. https://doi.org/10.1016/j.proghi.2016.01.001
22.
KempermannGKuhnHGGageFH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature386(6624): 493–495. https://doi.org/10.1038/386493a0
23.
KilkennyCBrowneWCuthillIC, et al. (2010) Animal research: Reporting in vivo experiments: The ARRIVE guidelines. British Journal of Pharmacology160(7): 1577–1579. https://doi.org/10.1111/j.1476-5381.2010.00872.x
24.
LahmyVMeunierJMalmströmS, et al. (2013) Blockade of Tau hyperphosphorylation and Aβ1-42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ1 receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology38(9): 1706–1723. https://doi.org/10.1038/npp.2013.70
25.
LazarovORobinsonJTangYP, et al. (2005) Environmental enrichment reduces Ab levels and amyloid deposition in transgenic mice. Cell120(5): 701–713. https://doi.org/10.1016/j.cell.2005.01.015
26.
LiLXuBZhuY, et al. (2010) DHEA prevents Aβ25-35-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling. Neuropharmacology59(4–5): 323–333. https://doi.org/10.1016/j.neuropharm.2010.02.009
27.
LucasGRymarVVSadikotAF, et al. (2008) Further evidence for an antidepressant potential of the selective sigma1 agonist SA 4503: Electrophysiological, morphological and behavioural studies. International Journal of Neuropsychopharmacology11(4): 485–495. https://doi.org/10.1017/S1461145708008547
28.
MacfarlaneSGrimmerTTeoK, et al. (2025) Blarcamesine for the treatment of early Alzheimer’s disease: Results from the ANAVEX2-73-AD-004 phase IIB/III trial. The Journal of Prevention of Alzheimer’s Disease12(1): 100016. https://doi.org/10.1016/j.tjpad.2024.100016
29.
Martínez-OrozcoHBencomo-MartínezAMaya-ArteagaJP, et al. (2025) CNEURO-201, an anti-amyloidogenic agent and σ1-receptor agonist, improves cognition in the 3xtg mouse model of Alzheimer’s disease by multiple actions in the pathology. International Journal of Molecular Sciences26(3): 1301. https://doi.org/10.3390/ijms26031301
30.
MauriceTLockhartBPPrivatA (1996) Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction. Brain Research706(2): 181–193. https://doi.org/10.1016/0006-8993(95)01032-7
31.
MauriceTMustafaMHDesrumauxC, et al. (2013) Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ25-35 nontransgenic mouse model of Alzheimer’s disease. Journal of Psychopharmacology27(11): 1044–1057. https://doi.org/10.1177/0269881113494939
32.
MauriceTGoguadzeN (2017) Sigma-1 (σ1) Receptor in memory and neurodegenerative diseases. Handbook of Experimental Pharmacology244: 81–108. https://doi.org/10.1007/164_2017_15
33.
MauriceT (2021) Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders. Expert Opinion on Drug Discovery16(4): 373–389. https://doi.org/10.1080/17460441.2021.1838483
34.
MarrazzoACaraciFSalinaroET, et al. (2005) Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport16(11): 1223–1226. https://doi.org/10.1097/00001756-200508010-00018
35.
Mercerón-MartínezDAlacán RicardoLBejeranoPina A, et al. (2024) Amylovis-201 enhances physiological memory formation and rescues memory and hippocampal cell loss in a streptozotocin-induced Alzheimer’s disease animal model. Brain Research1831: 148848. https://doi.org/10.1016/j.brainres.2024.148848
36.
MeunierJIeniJMauriceT (2006) The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. British Journal of Clinical Pharmacology149(8): 998–1012. https://doi.org/10.1038/sj.bjp.0706927
37.
OlsonAKEadieBDErnstC, et al. (2006) Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus16(3): 250–260. https://doi.org/10.1002/hipo.20157
38.
PaxinosGFranklinKBJ (2004) The Mouse Brain in Stereotaxic Coordinates, 2nd edn.Elsevier Science.
39.
Rivera-MarreroSBencomo-MartínezAOrta SalazarE, et al. (2020) A new naphthalene derivative with anti-amyloidogenic activity as potential therapeutic agent for Alzheimer’s disease. Bioorganic & Medicinal Chemistry28(20): 115700. https://doi.org/10.1016/j.bmc.2020.115700
40.
Rodríguez CruzYStrehaianoMRodríguez ObayaT, et al. (2017) An intranasal formulation of erythropoietin (Neuro-EPO) prevents memory deficits and amyloid toxicity in the APPSwe transgenic mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease55(1): 231–248. https://doi.org/10.3233/JAD-160500
41.
RuscherKShamlooMRickhagM, et al. (2011) The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain134(Pt 3): 732–746. https://doi.org/10.1093/brain/awq367
42.
SelkoeDJ (2013) The therapeutics of Alzheimer’s disease: Where we stand and where we are heading. Annals of Neurology74(3): 328–336. https://doi.org/10.1002/ana.24001
43.
SuTPSuTCNakamuraY, et al. (2016) The sigma-1 receptor as a pluripotent modulator in living systems. Trends in Pharmacological Sciences37(4): 262–278. https://doi.org/10.1016/j.tips.2016.01.003
Van PraagHKempermannGGageFH (2000) Neural consequences of environmental enrichment. Nature Reviews Neuroscience1(3): 191–198. https://doi.org/10.1038/35044558
46.
VaversEZvejnieceLMauriceT, et al. (2019) Allosteric modulators of sigma-1 receptor: A review. Frontiers in Pharmacology10: 223. https://doi.org/10.3389/fphar.2019.00223
47.
VillardVEspallerguesJKellerE, et al. (2011) Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. Journal of Psychopharmacology25(8): 1101–1117. https://doi.org/10.1177/0269881110379286
48.
WolfSAKronenbergGLehmannK, et al. (2006) Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biological Psychiatry60(12): 1314–1323. https://doi.org/10.1016/j.biopsych.2006.04.004
49.
YoungDLawlorPALeoneP, et al. (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Medicine5(4): 448–453. https://doi.org/10.1038/7449
50.
ZussyCBrureauAKellerE, et al. (2013) Alzheimer’s disease related markers, cellular toxicity and behavioral deficits induced six weeks after oligomeric amyloid-β peptide injection in rats. PLoS One8(1): e53117. https://doi.org/10.1371/journal.pone.0053117
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
