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. doi: 10.3233/JAD-161236.


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.

Keywords: 5XFAD mouse model; P2Y receptors; amyloid-β aggregates; behavioral disinhibition; metal-ion chelation; neuroprotection; nucleotides; spatial working memory.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Animals, Newborn
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / therapeutic use*
  • Biocompatible Materials / chemistry
  • Biocompatible Materials / therapeutic use*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Copper / therapeutic use
  • Disease Models, Animal
  • L-Lactate Dehydrogenase / metabolism
  • Maze Learning / physiology
  • Memory Disorders / etiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism
  • Phenothiazines / therapeutic use*
  • Platelet Aggregation / drug effects
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Zinc / therapeutic use


  • 2-S-methyl-adenosine 5'-O-(1-thiodiphosphate)
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antipsychotic Agents
  • Biocompatible Materials
  • Phenothiazines
  • Presenilin-1
  • 2-chloro-10-(4'(N-beta-hydroxyethyl)piperazinyl-1')acetylphenothiazine
  • Copper
  • L-Lactate Dehydrogenase
  • Zinc
  • Adenosine