Epidemiological studies indicate that isolated persons have increased risk of developing Alzheimer's disease (AD). This study investigated the cellular mechanisms of how social isolation influenced amyloid β peptide (Aβ) accumulation and affected the severity of AD-associated cognitive decline in a mouse model of AD. Amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice were placed either in isolation or in group from postnatal day 28 and tested for cognitive performance at the age of 3 months with fear-conditioning paradigms. We found that social isolation accelerated impairment of contextual fear memory in the APP/PS1 mice. The magnitude of long-term potentiation in the hippocampal CA1 neurons was significantly lower in the isolated APP/PS1 mice compared with group APP/PS1 and wild-type mice. Hippocampal level of Aβ was significantly elevated in the isolated APP/PS1 mice, which was accompanied by an increased calpain activity and p25/p35 ratio. In addition, surface expression of GluR1 subunit of AMPA receptor was decreased by social isolation. The association of p35, and α-CaMKII was significantly less in the isolated APP/PS1 mice indicating that their interaction was impaired. These results suggest that social isolation exacerbates memory deficit by increasing Aβ level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, α-CaMKII, and GluR1, resulting in the endocytosis of AMPA receptors.