Plasma Cortisol and Progression of Dementia in Subjects With Alzheimer-Type Dementia

Csernansky, John G.; Dong, Hongxin; Fagan, Anne M.; Wang, Lei; Xiong, Chengjie; Holtzman, David M.; Morris, John C.

doi:10.1176/ajp.2006.163.12.2164

Cited by 329 publications

(165 citation statements)

References 55 publications

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“…The dysregulation in the negative corticosteroid feedback, as well as increased corticosteroid levels, is reported in AD patients and preclinical mouse models [18]. This is supported by the evidence that increased plasma levels have been reported in the early stages of AD patients [19, 20] and decreased sensitivity to low-dose dexamethasone suppression [6]. Similarly, patients with sporadic AD have increased plasma cortisol levels during the onset and later stages [21-23].…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 87%

“…In this regard, Morgese et al [27] demonstrated that early life dietary deficiency in rats resulted in HPA axis hyperactivity and depression-like behavior, with elevated Aβ levels. Neuroendocrine disorders lead to memory deficit and cognitive dysfunction(s) with a high concentration of glucocorticoids in serum resulting in the extensive loss of neurons in the brain thereby progressing to AD symptoms [20]. Brureau et al [28] suggested that elevated glucocorticoids may be the first consequence of amyloid toxicity in a preclinical rat model of AD.…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

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Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Ahmad

Fatima

Mondal³

2019

Neuropsychobiology

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Alzheimer’s disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.

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Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 87%

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Ahmad

Fatima

Mondal³

2019

Neuropsychobiology

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“…Glucocorticoid (cortisol) levels in AD patients are elevated relative to age-matched controls, and several lines of evidence support a role of stress steroids in Aβ regulation (reviewed in [39]). Although glucocorticoids would appear to be an important target in AD, administration of steroids in human AD trials does not alter cognition (ADCS Prednisone Trial [40]) and results of studies from AD rodent models have been mixed [17, 23, 37, 41–46]. …”

Section: Discussionmentioning

confidence: 99%

Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease

Campbell

Zhang

Roe

et al. 2015

JAD

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Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer’s disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-β (Aβ) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in an AD transgenic model and whether this type of treatment could impact Aβ pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1+/−) and homozygous (PSAPP-R1−/−) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Aβ levels and pathology. We found that both PSAPP-R1+/− and PSAPP-R1−/− had significantly reduced Aβ burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Aβ peptides and AβPP-CTFs, providing support for a direct relationship between CRFR1 and Aβ production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Aβ neuropathology.

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“…Stress has been increasingly recognized as an external factor that can impact the onset and progression of AD (Dong et al, 2004; Wilson et al 2006; Csernansky et al, 2006; Huang et al, 2010; Alkadhi, 2012). Although the mechanisms involved in the effects of stress on the pathogenesis of AD remain unclear, there is growing evidence that CRF and CRF1 receptors play a critical role in the production and aggregation of both Aβ and tau (Kang et al, 2007; Rissman et al, 2007; Carroll et al, 2011; Rissman et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…For example, individuals prone to psychological distress are twice as likely to develop AD (Wilson et al, 2005; Wilson et al, 2006). Elevated plasma cortisol levels, often an indicator of stress, have been reported in patients with AD (Swanwick et al, 1998; Umegaki et al, 2000; Rehman, 2002), and higher plasma cortisol levels were correlated with severity of cognitive decline in AD patients (Csernansky et al, 2006). Considering other elements of the HPA axis, investigators have reported a reduction in corticotropin releasing factor (CRF) immunoreactive cells and increases in the density of postsynaptic CRF receptors in the brain of AD patients (Whitehouse et al, 1987; Pomara et al, 1989; Behan et al, 1995; De Souza, 1995).…”

Section: Introductionmentioning

confidence: 99%

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

Dong

Wang²,

Zeng

et al. 2014

Psychopharmacology

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Rationale Previous studies indicate that psychosocial stressors could accelerate amyloid-β (Aβ) levels and accelerate plaque deposition in mouse models of Alzheimer disease (AD). Stressors enhanced the release of corticotrophin-releasing factor (CRF) and exogenous CRF administration mimicked the effects of stress on Aβ levels in mouse models of AD. However, whether CRF receptor 1 (CRF1) antagonists could influence the stress-induced acceleration of an AD-like process in mouse models has not been well studied. Objective We sought to examine whether CRF1 antagonists inhibit the effects of isolation stress on tissue Aβ levels, Aβ plaque deposition, and behaviors related to anxiety and memory in Tg2576 mice, and to investigate the molecular mechanism underlying such effects. Methods Cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, then the subgroups of these cohorts received daily intraperitoneal injections of the CRF1 antagonists, antalarmin or R121919 (5, 10 and 20 mg/kg), or vehicle for 1 week. Other cohorts of Tg2576 mouse pups were isolated or group housed at 21 days of age, and then at 4 months of age, subgroups of these mice were administered antalarmin (20 mg/kg) or vehicle in their drinking water for 6 months. Finally, cultured primary hippocampal neurons from regular Tg2576 pups (P0) were incubated with CRF (0.1, 1 and 10nM), antalarmin (100 nM) or H-89 (1 μM) for 48 hours. Brain tissues or cultured neurons were collected for histological and biochemical analyses, and behavioral measures were collected in the cohorts of mice that were chronically stressed. Results Administration of antalarmin at 20 mg/kg dose for 1 week significantly reduced Aβ1-42 levels in isolation stressed mice. Administration of antalarmin for 6 months significantly decreased plasma corticosterone levels, tissue Aβ1-42 levels and Aβ plaque deposition in the brain and blocked the effects of isolation stress on behaviors related to anxiety and memory. Finally, incubation of neurons with 100 nM antalarmin inhibited the ability of 10 nM CRF to increase Aβ1-42 levels and protein kinase A IIβ (PKAIIβ) expression. The effect of CRF1 on Aβ1-42 levels was also diminished by treatment with H-89, a c-AMP/PKA inhibitor. Conclusions These results suggest that CRF1 antagonists can slow an AD-like process in Tg2576 mice, and that the c-AMP/PKA signaling pathway may be involved in this effect.

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Plasma Cortisol and Progression of Dementia in Subjects With Alzheimer-Type Dementia

Abstract: Higher HPA activity, as reflected by increased plasma cortisol levels, is associated with more rapid disease progression in subjects with Alzheimer-type dementia.

Cited by 329 publications

References 55 publications

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice

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