Long-Term Treatment with Fluoroethylnormemantine (FENM)\nAlleviated Memory Deficits, Amyloid Pathology, and Microglial Reaction\nin APP/PS1 Mice

Fluoroethylnormemantine\n(FENM, RST-01) shows different pharmacological\nproperties from Memantine. The drug is neuroprotective in pharmacological\nand transgenic mouse models of Alzheimer’s disease (AD), particularly\nlimiting the neuroinflammatory response to amyloid-β (Aβ)\naccumulation. In order to define early therapeutic intervention aimed\nat preventing AD and targeting the early activation of proinflammatory\npathways, we examined the impact of chronic FENM treatment starting\npresymptomatically in APP<sub>swe</sub>/PSEN1<sup>∂E9</sup> (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type\n(WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day)\nin the drinking bottle between 3 and 12 months of age. They were tested\nonce a month for spontaneous alternation and, at the end of the treatment,\nfor object recognition, water-maze learning, and passive avoidance.\nAmyloid plaques, astrocytes, and microglia were assessed by immunofluorescence,\nand guanidine-soluble and insoluble Aβ<sub>1–40/42</sub> levels were determined in the hippocampal formation. Spontaneous\nalternation performances regularly decreased in APP/PS1, but not in\nWT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit.\nAt 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant\nimprovements in all behavioral procedures tested. The astroglial reaction\nwas not significantly attenuated by FENM in the <i>stratum radiatum</i>, <i>stratum moleculare,</i> and polymorph layer of the\ndentate gyrus. The microglial reaction was significantly decreased\nin the two latter areas. In the polymorph layer, a significant effect\non amyloid plaques was measured. Global analyses of amyloid load showed\nattenuations of soluble and insoluble Aβ<sub>1–40</sub> levels and a significant decrease in the level of insoluble Aβ<sub>1–42</sub>. Moreover, significant negative correlations were\nobserved for FENM impacts on amyloid load or microglial activation\nand the alternation score. FENM confirmed, under a chronic presymptomatic\ntreatment, its neuroprotective efficacy in AD. Our data particularly\nsuggested that an impact on Aβ and microglia could be related\nto the preservation of cognitive functions.