Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice
The study investigated effects of CHF5074 on AD neuropathology, spine density/morphology, cell cycle, microglia activity, and cognitive impairment in Tg2576 mice. CHF5074 is a nonsteroidal anti-inflammatory derivative devoid of cyclooxygenase inhibitory activity. In vitro, CHF5074 behaves as a γ secretase modulator preferentially inhibiting Aβ42 production. CHF5074 has been shown to inhibit brain plaque deposition and to attenuate or reverse contextual and spatial memory deficit in different transgenic mouse models of AD, also reversing long-term potentiation deficit in the hippocampus. However, recent data have shown that CHF5074 is able to promote axon growth and astrocyte plasticity by modulating Rho-GTPase-dependent signaling. In this study, the effects of a long-term (13-month) treatment with CHF5074 on indicators of brain functionality and neurodegeneration in transgenic Tg2576 mice were assessed and compared with those induced by a prototypical γ-secretase inhibitor (DAPT).Tg2576 mice fed with standard diet displayed an impairment of recognition memory. This deficit was completely reverted by the higher dose of CHF5074, while no effects were observed in DAPT-treated mice. Similarly, amyloid plaque burden, microglia activation and aberrant cell cycle events were significantly affected by CHF5074, but not DAPT, treatment. Both CHF5074 and DAPT reduced intraneuronal Aβ content, also increasing Aβ40 and Aβ42 plasma levels. This comparative analysis revealed a profoundly diverse range of clinically relevant effects differentiating the multifunctional anti-inflammatory derivative CHF5074 from the γ-secretase inhibitor DAPT and highlighted unique mechanisms and potential targets that may be crucial for neuroprotection in mouse models of AD.
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