Glucocorticoids may initiate Alzheimer's disease: A Potential therapeutic role for mifepristone (RU-486)
ABSTRACT Alzheimer's disease (AD) is a relentless neurodegenerative disease of uncertain etiology affecting millions worldwide. Stress is an important etiological factor associated with AD. Stress and glucocorticoids (GCs) are intimately related; so much so that stress is considered to be "a condition that is able to liberate GCs". Normally, GCs are required for various bodily functions but their excess is deleterious. Hippocampus has highest density of GC receptors in brain, is particularly vulnerable to their damaging effects and undergoes reversible atrophy under their influence. Hippocampal atrophy is an initial event for the development of AD, the most common form of dementia. Apart from atrophy, GCs are able to produce a variety of other initial structural and functional changes in hippocampus. For example, these down regulate GC receptors, leading to disruption in negative feedback loop, alter dendtritic morphology and impair axonal transport. Impaired axon transport is probably an initial event that leads to the formation of paired helical filaments. Additionally, they inhibit insulin-degrading enzyme, which degrades A-beta; consequently reducing its clearance. Since GCs mediate a number of initial events in AD pathogenesis, therefore GC antagonists (e.g. mifepristone) can be tried. Mifepristone has intrinsic neuroprotective and antioxidant potential which could offer additional benefits as well. Use of this drug therefore, in those with mild AD or with milder cognitive impairment can be useful. Appropriate dose, duration, safety and efficacy need to be worked out.
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- "hippocampal GluT4 (Piroli, Grillo et al. 2007), so that insulin resistance might well interact with GC signaling; indeed, removal of adrenal steroids increases sensitivity to central insulin (Chavez, Seeley et al. 1997), suggesting a bidirectional modulation of neural function. GCs have been suggested as a potential causal agent for conditions including Alzheimer's disease, associated with impaired insulin signaling (Dhikav and Anand 2007), and cause impaired neuronal and glial glucose usage (Sapolsky 1986; Brunetti, Fulham et al. 1998; Gip, Hagiwara et al. 2004) whereas damage caused by elevation of GCs can be reversed by supplying additional fuel (Saposky 1986). Moreover, GCs have multiple deleterious effects in the hippocampus, including interference with neurogenesis, and neurogenesis is associated with enhanced memory performance but impaired in T2DM (Gould, Beylin et al. 1999; Drapeau, Mayo et al. 2003; Cao, Jiao et al. 2004; Aimone, Wiles et al. 2006; Lindqvist, Mohapel et al. 2006; Ramirez-Amaya, Marrone et al. 2006; Dupret, Revest et al. 2008; Fontan-Lozano, Lopez-Luch et al. 2008; Lafenêtre, Leske et al. 2009; Lang, Yan et al. 2009; Stangl and Thuret 2009; Deng, Aimone et al. 2010; van der Borght, Kohnke et al. 2011), further suggesting a possible role for GCs in the etiology of cognitive deficits associated with insulin resistance. "
ABSTRACT: Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding, to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cognitive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients.Neurobiology of Learning and Memory 08/2011; 96(3):432-42. DOI:10.1016/j.nlm.2011.08.005 · 4.04 Impact Factor
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- "Thus, a recently developed view suggests that hypercortisolemia, leading to hippocampal atrophy and further HPA axis disinhibition (i.e. " the glucocorticoid cascade hypothesis " ), would peer-00511184, version 1 -24 Aug 2010 Solas M 4 initiate a chain of events, ultimately culminating in the development of lesions typical of AD (Dhikav and Anand, 2007). The mechanisms underlying the effects of altered glucocorticoid levels remain largely unknown. "
ABSTRACT: There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease. Glucocorticoid secretion associated with early life stress may contribute to the variability of the aging process and to the development of neuro- and psychopathologies. Maternal separation (MS), a model of early life stress in which rats experience 3 h of daily separation from the dam during the first 3 weeks of life, was used to study the interactions between stress and aging. Young (3 months) MS rats showed an altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, depressive-like behavior in the Porsolt swimming test and cognitive impairments in the Morris water maze and new object recognition test that persisted in aged (18 months) rats. Levels of insulin receptor, phosphorylated insulin receptor and markers of downstream signaling pathways (pAkt, pGSK3 beta, pTau, and pERK1 levels) were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker ARC in MS aged rats compared with single MS or aged rats. It is interesting to note that there was a significant increase in the C99 : C83 ratio, A beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that in aged rats subjected to early life stress, there was an increase in the amyloidogenic processing of amyloid precursor protein (APP). These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of Alzheimer disease (AD). The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2010; 35(8):1664-73. DOI:10.1038/npp.2010.13 · 7.83 Impact Factor
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- "Neuroprotective agents may be able to help reduce further degeneration, although it is unknown whether this would have a large enough effect on the overall pathology of AD. The glucocorticoid antagonist mifepristone has recently been suggested as a neuroprotective treatment for AD (Dhikav and Anand 2007). Stress has been suggested as a factor that contributes to the development of Alzheimer's (Miller and O'Callaghan 2005); therefore, inhibiting glucocorticoid may help protect against AD-related cellular degeneration. "
ABSTRACT: Alzheimer's disease (AD) is an incurable neurodegenerative disorder that produces cognitive impairments that increase in severity as the disease progresses. The clinical symptoms are related to the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex which represent the pathophysiological hallmarks of AD. The debilitating nature of the disease can result in clinical burden for the patient, emotional strain for those that care for patients with Alzheimer's, and significant financial burden to society. The goals of current treatments, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist, are to reduce the severity or slow the progression of cognitive symptoms. Although these treatments have demonstrated modest clinical benefit, they are unable to prevent, prohibit, or reverse the underlying pathophysiology of AD. Considerable progress has been made toward the development of disease-modifying treatments. Treatments currently under development mainly target the production, aggregation, and removal of existing amyloid beta-peptide aggregates which are believed to instigate the overall development of the neuropathology. Additional strategies that target tau pathology are being studied to promote neural protection against AD pathology. The current research has continued to expand our knowledge toward the development of disease modifying Alzheimer's therapies; however, no specific treatment strategy capable of demonstrating empirical efficacy and safety has yet to emerge.Neuropsychiatric Disease and Treatment 09/2008; 4(4):765-77. · 2.15 Impact Factor