A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer's Disease in 5XFAD Mice.
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.
['Segal-Gavish|Hadar|H|', 'Danino|Ortal|O|', 'Barhum|Yael|Y|', 'Ben-Zur|Tali|T|', 'Shai|Ella|E|', 'Varon|David|D|', 'Offen|Daniel|D|', 'Fischer|Bilha|B|']
D000241:Adenosine D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D000818:Animals D000831:Animals, Newborn D014150:Antipsychotic Agents D001672:Biocompatible Materials D002478:Cells, Cultured D002540:Cerebral Cortex D003300:Copper D004195:Disease Models, Animal D007770:L-Lactate Dehydrogenase D018782:Maze Learning D008569:Memory Disorders D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009474:Neurons D010640:Phenothiazines D010974:Platelet Aggregation D053764:Presenilin-1 D015032:Zinc
metal-ion chelation neuroprotection 5XFAD mouse model behavioral disinhibition spatial working memory P2Y receptors amyloid-β aggregates nucleotides