Presenilin 2 mutation accelerates the onset of impairment in trace eyeblink conditioning in a mouse model of Alzheimer's disease overexpressing human mutant amyloid precursor protein

► Tested trace eyeblink conditioning in APP/PS2 transgenic AD model (PS2Tg2576) mice. ► PS2Tg2576 mice aged 3 months showed normal performance in trace conditioning. ► Impaired trace conditioning in PS2Tg2576 mice at ages 4, 6, and 12 months. ► Intact trace conditioning in Tg2576 APPsw mice at age 4 months. ► PS2 mutation accelerates the onset of cognitive impairment in trace conditioning. Missense mutations in 2 homologous genes, presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. The purpose of the present study was to investigate whether PS2 mutation accelerates the onset of trace eyeblink conditioning deficits in an Alzheimer's disease (AD) mouse model overexpressing human amyloid precursor protein (APP) with the Swedish mutation (K670N, M671L) (Tg2576 mice). For this purpose, a double-transgenic mouse (PS2Tg2576 mice) was produced by cross-breeding transgenic mice carrying human mutant PS2 (N141I) with Tg2576 mice. Long-trace interval (trace interval=500ms) eyeblink conditioning was tested in the PS2Tg2576 mice at ages 3, 4, 6, and 12 months. At 3 months, PS2Tg2576 mice exhibited normal acquisition of conditioned responses (CRs) during trace eyeblink conditioning, whereas trace conditioning was significantly impaired in PS2Tg2576 mice at ages 4, 6, and 12 months. In contrast, Tg2576 mice showed intact memory performance during trace conditioning at 4 months. This cross-sectional study clearly indicates that PS2 mutation significantly accelerates the onset of cognitive impairment in associative trace eyeblink memory.