Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress

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.

Section: Acceleration Of Memory Impairment By Social Isolationsupporting

confidence: 92%

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

Hsiao

Chen

et al. 2011

“…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).…”

Section: Introductionsupporting

confidence: 87%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Lanté

Chafaï

Raymond

et al. 2015

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.

“…Our findings that chronic isolation significantly impaired contextual fear conditioning and spatial memory, but not auditory-cued fear conditioning or nonspatial performance in the water maze are consistent with previous reports that either acute (Barrientos et al, 2003) or chronic (Kogan et al, 2000;Bianchi et al, 2006) isolation markedly impaired hippocampal-dependent memory, but not memory that does not depend on hippocampal functioning. Previous studies on the effects of chronic stress on hippocampal neurogenesis demonstrated decreased cell proliferation in the dentate gyrus following chronic isolation (Dong et al, 2004), as well as several other chronic stressors (Simon et al, 2005; Lee et al, 2006;. Chronic social isolation also exacerbated the effect of another chronic stressor (daily foot-shock for 3 weeks) on the production of new hippocampal neurons (Westenbroek et al, 2004), and precluded the positive influence of short-term running on neurogenesis (Stranahan et al, 2006).…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, exposure to acute psychological stressors, such as short-term (3-5 h) isolation, increased hippocampal IL-1 levels and produced memory impairments that were completely blocked by an intrahippocampal injection of IL-1ra (Barrientos et al, 2003(Barrientos et al, , 2004. Stressful conditions, such as social isolation, also influence several aspects of neural plasticity, including hippocampal neurogenesis (Dong et al, 2004;Westenbroek et al, 2004;Stranahan et al, 2006), which is critically important for some hippocampal-dependent learning and memory tasks (Shors et al, 2001(Shors et al, , 2002Saxe et al, 2006;Winocur et al, 2006). We have recently demonstrated that chronic mild stress, as well as chronic administration of IL-1b, markedly reduces hippocampal neurogenesis .…”

Section: Introductionmentioning

confidence: 99%

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

Menachem-Zidon

Goshen

Kreisel

et al. 2007

128

The proinflammatory cytokine interleukin-1 (IL-1) within the brain is critically involved in mediating the memory impairment induced by acute inflammatory challenges and psychological stress. However, the role of IL-1 in memory impairment and suppressed neurogenesis induced by chronic stress exposure has not been investigated before now. We report here that mice that were isolated for 4 weeks displayed a significant elevation in hippocampal IL-1b levels concomitantly with body weight loss, specific impairment in hippocampaldependent memory, and decreased hippocampal neurogenesis. To examine the causal role of IL-1 in these effects, we developed a novel approach for long-term delivery of IL-1 receptor antagonist (IL-1ra) into the brain, using transplantation of neural precursor cells (NPCs), obtained from neonatal mice with transgenic overexpression of IL-1ra (IL-1raTG) under the glial fibrillary acidic protein promoter. Four weeks following intrahippocampal transplantation of IL-1raTG NPCs labeled with PKH-26, the transplanted cells were incorporated within the dentate gyrus and expressed mainly astrocytic markers. IL-1ra levels were markedly elevated in the hippocampus, but not in other brain regions, by 10 days and for at least 4 weeks post-transplantation. Transplantation of IL-1raTG NPCs completely rescued the chronic isolation-induced body weight loss, memory impairment, and suppressed hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham operated. The transplantation had no effect in group-housed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic isolation and suggest that transplantation of IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in chronic inflammatory and neurological conditions.