1. Academic Validation
  2. Brain toxicity and inflammation induced in vivo in mice by the amyloid-β forty-two inducer aftin-4, a roscovitine derivative

Brain toxicity and inflammation induced in vivo in mice by the amyloid-β forty-two inducer aftin-4, a roscovitine derivative

  • J Alzheimers Dis. 2015;44(2):507-24. doi: 10.3233/JAD-140711.
Johann Meunier 1 Nozha Borjini 1 Cyril Gillis 1 Vanessa Villard 1 Tangui Maurice 2
Affiliations

Affiliations

  • 1 Amylgen, Montferrier-sur-Lez, France.
  • 2 Amylgen, Montferrier-sur-Lez, France INSERM U. 710, University of Montpellier 2, Montpellier, France.
Abstract

Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of Amyloid-β (Aβ)1-42 from Amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase Inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.

Keywords

A$\beta_{1-42}$; Alzheimer's disease; aftins; amyloid toxicity in vivo; memory deficits.

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