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A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice.

Abstract

BACKGROUND

Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer's disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5'-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant.

OBJECTIVE

To further explore SAS ability to protect the brain from Aβ toxicity both in vitro and in vivo.

METHODS

We evaluated SAS ability to decompose or inhibit the formation of Aβ42-M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD.

RESULTS

We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42-Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months.

CONCLUSION

Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model.

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  • Authors+Show Affiliations

    ,

    Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    ,

    Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.

    ,

    Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    ,

    Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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    Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.

    ,

    Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.

    ,

    Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.

    Source

    MeSH

    Adenosine
    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Animals
    Animals, Newborn
    Antipsychotic Agents
    Biocompatible Materials
    Cells, Cultured
    Cerebral Cortex
    Copper
    Disease Models, Animal
    L-Lactate Dehydrogenase
    Maze Learning
    Memory Disorders
    Mice
    Mice, Inbred C57BL
    Mice, Transgenic
    Neurons
    Phenothiazines
    Platelet Aggregation
    Presenilin-1
    Zinc

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28453480

    Citation

    Segal-Gavish, Hadar, et al. "A Multifunctional Biocompatible Drug Candidate Is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice." Journal of Alzheimer's Disease : JAD, vol. 58, no. 2, 2017, pp. 389-400.
    Segal-Gavish H, Danino O, Barhum Y, et al. A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. J Alzheimers Dis. 2017;58(2):389-400.
    Segal-Gavish, H., Danino, O., Barhum, Y., Ben-Zur, T., Shai, E., Varon, D., ... Fischer, B. (2017). A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. Journal of Alzheimer's Disease : JAD, 58(2), pp. 389-400. doi:10.3233/JAD-161236.
    Segal-Gavish H, et al. A Multifunctional Biocompatible Drug Candidate Is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. J Alzheimers Dis. 2017;58(2):389-400. PubMed PMID: 28453480.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice. AU - Segal-Gavish,Hadar, AU - Danino,Ortal, AU - Barhum,Yael, AU - Ben-Zur,Tali, AU - Shai,Ella, AU - Varon,David, AU - Offen,Daniel, AU - Fischer,Bilha, PY - 2017/4/30/pubmed PY - 2018/3/17/medline PY - 2017/4/29/entrez KW - 5XFAD mouse model KW - P2Y receptors KW - amyloid-β aggregates KW - behavioral disinhibition KW - metal-ion chelation KW - neuroprotection KW - nucleotides KW - spatial working memory SP - 389 EP - 400 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 58 IS - 2 N2 - BACKGROUND: Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer's disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5'-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant. OBJECTIVE: To further explore SAS ability to protect the brain from Aβ toxicity both in vitro and in vivo. METHODS: We evaluated SAS ability to decompose or inhibit the formation of Aβ42-M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD. RESULTS: We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42-Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months. CONCLUSION: Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/28453480/A_Multifunctional_Biocompatible_Drug_Candidate_is_Highly_Effective_in_Delaying_Pathological_Signs_of_Alzheimer's_Disease_in_5XFAD_Mice_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-161236 DB - PRIME DP - Unbound Medicine ER -