Bibliographic
Memantine, a noncompetitive NMDA receptor antagonist with neuroprotective properties, has been used for the treatment of Alzheimer's disease (AD). Administration of memantine to various transgenic AD mice has been reported to improve cognitive deficits, very often completely back to normal wild-type control levels. However, the efficacy of memantine in preclinical studies has not translated to the clinic; results show only marginal and transient efficacy in moderate to severe AD. To further address the preclinical efficacy of memantine the authors, in this study, compared in vivo efficacy of subchronic memantine (once daily for 30 days) in the 5XFAD mouse model harboring moderate (6–7 months of age) and robust (12–15 months) Aβ accumulation in brain. Treatments with memantine (10 mg/kg, i.p.) reversed memory impairments in the younger 5XFAD mice, as tested by the contextual fear conditioning and spontaneous alternation Y-maze paradigms. Compared to vehicle, memantine treatment had no effects on soluble Aβ oligomer or total Aβ42 levels in 5XFAD mouse brains, indicating that the cognitive benefits of memantine in this AD model are not due to its direct effect on β-amyloidosis. In contrast, subchronic treatment (10mg/kg i.p.) of older 5XFAD mice with memantine showed no behavioral benefit. The older mice exhibited more profound memory deficits that correlated with increases in cerebral levels of soluble Aβ oligomers. A higher dose (30 mg/kg) of memantine impaired memory performances in wild-type controls, therefore confounding behavioral outcomes in 5XFAD mice. In summary, this study showed that memantine treatment rescued memory impairments in young 5XFAD mice without affecting cerebral Aβ levels, whereas it did not ameliorate the profound cognitive deficits observed in older mice that exhibited high levels of cerebral soluble Aβ oligomers.