Mutations in
presenilin 1 (PS1) and
presenilin 2 (PS2) are known to cause early onset of
Alzheimer's disease (AD). These
proteins comprise the catalytic domain of γ-
secretase, which catalyzes the cleavage of β-
amyloid (Aβ) from
amyloid precursor
protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular
calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of
cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of
presenilins by small molecules may have therapeutic potential for the treatment of
cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-
secretase modulator (GSM), reduced Aβ production and ameliorated
cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single
oral administration of compound-1 at 1 and 3mg/kg ameliorated
cognitive dysfunction in aged non-transgenic mice. Moreover, compound-1 enhanced synaptic plasticity in hippocampal slices from aged C57BL/6J mice and increased
messenger RNA (
mRNA) expression of the immediate early gene c-fos, which has been shown to be related to synaptic plasticity in vivo. Finally, compound-1 modulated Ca(2+) signals through PS1 in mouse embryonic fibroblast cells. Taken together, compound-1 ameliorates both Aβ pathology and age-related
cognitive dysfunctions. Hence, compound-1 may have potential as an early intervention for the
cognitive declines that are commonly diagnosed in aged subjects, such as
mild cognitive impairment (MCI) and prodromal AD.