Chronic stress accelerates learning and memory impairments and increases amyloid deposition in APP_V717I‐CT100 transgenic mice, an Alzheimer's disease model

Abstract

Although chronic stress is known to be linked with memory and other neurological disorders, little is known about the relationship between chronic stress and the onset or development of Alzheimer's disease (AD). In this study, we investigated the effects of long-term stress on the onset and severity of cognitive deficits and pathological changes in APPV717I-CT100 mice overexpressing human APP-CT100 containing the London mutation (V717I) after exposure to immobilization stress. We found that chronic immobilization stress accelerated cognitive impairments, as accessed by the Passive avoidance and the Social Transfer of Food Preference (STFP) tests. Moreover, the numbers and densities of vascular and extracellular deposits containing amyloid beta peptide (Abeta) and carboxyl-terminal fragments of amyloid precursor protein (APP-CTFs), which are pathologic markers of AD, were significantly elevated in stressed animals, especially in the hippocampus. Moreover, stressed animals, also showed highly elevated levels of neurodegeneration and tau phosphorylation and increased intraneuronal Abeta and APP-CTFs immunoreactivities in the hippocampus and in the entorhinal and piriform cortex. This study provides the first evidence that chronic stress accelerates the onset and severity of cognitive deficits and that these are highly correlated with pathological changes, which thus indicates that chronic stress may be an important contributor to the onset and development of AD.

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

“…It is likely that social isolation led to oxidative stress (Schiavone et al, 2009), which in turn stimulated b-and g-secretase activity (Chan et al, 2009) resulting in increased Ab, which then triggered onset of cognition decline in the APP/PS1 mice. These results are consistent with previous reports showing that stress and glucocorticoids similarly promote APP processing along the amyloidogenic pathway (Catania et al, 2009) resulting in the exacerbation of AD-like neuropathology (Billings et al, 2005;Green et al, 2006;Jeong et al, 2006;Srivareerat et al, 2009).…”

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

“…This is in line with the observations that major stressful events lower the age of onset of familial AD (Mejia et al, 2003). In various preclinical AD models, stress worsens deficits in hippocampus-dependent spatial learning (Catania et al, 2009;Cuadrado-Tejedor et al, 2012;Dong et al, 2004;Jeong et al, 2006;Srivareerat et al, 2009;Tran et al, 2010). These deleterious effects are in part caused by an accelerated accumulation of Ab under stressing conditions (Catania et al, 2009;Cuadrado-Tejedor et al, 2012;Dong et al, 2004;Green et al, 2006;Jeong et al, 2006;Srivareerat et al, 2009).…”

“…In various preclinical AD models, stress worsens deficits in hippocampus-dependent spatial learning (Catania et al, 2009;Cuadrado-Tejedor et al, 2012;Dong et al, 2004;Jeong et al, 2006;Srivareerat et al, 2009;Tran et al, 2010). These deleterious effects are in part caused by an accelerated accumulation of Ab under stressing conditions (Catania et al, 2009;Cuadrado-Tejedor et al, 2012;Dong et al, 2004;Green et al, 2006;Jeong et al, 2006;Srivareerat et al, 2009). Stress triggers the release of glucocorticoid hormones (CORT), the major output of the hypothalamopituitary-adrenal axis (HPA).…”

Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

“…The results of the present study demonstrate that chronic exposure to isolation can also be considered an IL-1-mediated condition. These findings may be relevant to previous reports that chronic stress can exacerbate the symptoms of other IL-1-mediated medical conditions, including Alzheimer's disease and MS (Wilson et al, 2003;Brown et al, 2006;Jeong et al, 2006). Long-term suppression of IL-1 signaling should be highly beneficial for any medical condition associated with excessive brain IL-1 production.…”