The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

Abstract

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 b peptide (Ab) 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 Ab 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 a-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 Ab level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, a-CaMKII, and GluR1, resulting in the endocytosis of AMPA receptors.

Social Isolation Exacerbates Schizophrenia-Like Phenotypes via Oxidative Stress in Cortical Interneurons

“…PWSI was also unable to induce a robust oxidative stress response, measured by DHE (Figure 1), anti-8-OH-dG or 4-HNE staining (Figure 3). These signs of murine resilience to PWSI stress, as recently reported in wild-type mice (52), appear to be in contrast to the recent reports in rats (4,53); however, underlying mechanisms explaining species’ differences are unclear since few such studies have been published with mice (54). …”

Decreased cerebral Irp‐1B limits impact of social isolation in wild type and Alzheimer's disease modeled in Drosophila melanogaster

“…In accordance with this study, environmental enrichment also affected the behavioral patterns of wild‐type mice . Moreover, there is evidence that social isolation exacerbated memory deficits in a murine AD model . In addition, social interaction could reverse memory deficits in APP/PS1 transgenic AD mice by increasing hippocampal neurogenesis .…”

The Role of Mental and Physical Activities against Development of Alzheimer ’s Disease in Socialized and Isolated Rats

“…These findings are in agreement with [65]. SI increases neuronal oxidative stress [66], which consecutively can stimulate β-and γ-secretase activity [67], resulting in Aβ elevation and cognition deficits, also stress promotes APP processing along the amyloidogenic pathway [65]. Social isolation can also exaggerate the inflammatory processes [68].…”