Long-Term Treatment with Fluoroethylnormemantine (FENM) Alleviated Memory Deficits, Amyloid Pathology, and Microglial Reaction in APP/PS1 Mice.

Abstract

Fluoroethylnormemantine (FENM, RST-01) shows different pharmacological properties from Memantine. The drug is neuroprotective in pharmacological and transgenic mouse models of Alzheimer's disease (AD), particularly limiting the neuroinflammatory response to amyloid-β (Aβ) accumulation. In order to define early therapeutic intervention aimed at preventing AD and targeting the early activation of proinflammatory pathways, we examined the impact of chronic FENM treatment starting presymptomatically in APP_swe/PSEN1^∂E9 (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type (WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day) in the drinking bottle between 3 and 12 months of age. They were tested once a month for spontaneous alternation and, at the end of the treatment, for object recognition, water-maze learning, and passive avoidance. Amyloid plaques, astrocytes, and microglia were assessed by immunofluorescence, and guanidine-soluble and insoluble Aβ_1-40/42 levels were determined in the hippocampal formation. Spontaneous alternation performances regularly decreased in APP/PS1, but not in WT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit. At 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant improvements in all behavioral procedures tested. The astroglial reaction was not significantly attenuated by FENM in the stratum radiatum, stratum moleculare, and polymorph layer of the dentate gyrus. The microglial reaction was significantly decreased in the two latter areas. In the polymorph layer, a significant effect on amyloid plaques was measured. Global analyses of amyloid load showed attenuations of soluble and insoluble Aβ_1-40 levels and a significant decrease in the level of insoluble Aβ_1-42. Moreover, significant negative correlations were observed for FENM impacts on amyloid load or microglial activation and the alternation score. FENM confirmed, under a chronic presymptomatic treatment, its neuroprotective efficacy in AD. Our data particularly suggested that an impact on Aβ and microglia could be related to the preservation of cognitive functions.