Dhikav V, Anand KS. Glucocorticoids may initiate Alzheimer's disease: a potential therapeutic role for mifepristone (RU-486). Med Hypotheses 68: 1088-1092

Dr. Ram Manohar Lohia Hospital, New Dilli, NCT, India
Medical Hypotheses (Impact Factor: 1.07). 02/2007; 68(5):1088-92. DOI: 10.1016/j.mehy.2006.09.038
Source: PubMed


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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    • "The principal constituent of amyloid plaques observed in AD is the Aβ protein, which is generated from APP. APP can be cleaved by BACE1 and α-secretase to produce C99 and C83. These C-terminal fragments can then be cleaved by γ-secretase to produce Aβ and p3, respectively [14]. It has been shown experimentally that stress/increased corticosterone levels provoke misprocessing of amyloid precursor Fig. 6. "
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    ABSTRACT: It is becoming evident that chronic exposure to stress might result not only in insulin resistance or cognitive deficits, but may also be considered a risk factor for pathologies such as depression or Alzheimer's disease (AD). There is great interest in determining the molecular mechanisms underlying interactions between stress, ageing, memory and Alzheimer´s disease (AD). We have used the chronic mild stress (CMS) model to study the effects of chronic stress on the ageing process and the development of central insulin resistance and AD pathology. CMS aged mice showed cognitive impairments in the novel object recognition test. In addition, CMS aged mice displayed both peripheral insulin resistance, as shown by HOMA index, and decreased hippocampal levels of pIRS and downstream intracellular signaling (pAKT, pGSK and pERK1/2). Interestingly, there was a significant increase in both C99:C83 ratio and BACE1 levels in the hippocampus of CMS aged mice. Increased expression of the AD marker pTau was also found in stressed aged mice. Increased expression of the stress-activated protein kinase JNK was found in CMS aged mice, accompanied by significant decreases in glucocorticoid receptor (GR) and increases in mineralocorticoid receptor (MR) expression. It is suggested that the interaction of stress with ageing should be considered when studying determinants of the onset and progression of AD.
    Biochimica et Biophysica Acta 09/2013; 1832(12). DOI:10.1016/j.bbadis.2013.09.013 · 4.66 Impact Factor
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    • "Depression[5668] "
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    ABSTRACT: Hippocampus is a complex brain structure embedded deep into temporal lobe. It has a major role in learning and memory. It is a plastic and vulnerable structure that gets damaged by a variety of stimuli. Studies have shown that it also gets affected in a variety of neurological and psychiatric disorders. In last decade or so, lot has been learnt about conditions that affect hippocampus and produce changes ranging from molecules to morphology. Progresses in radiological delineation, electrophysiology, and histochemical characterization have made it possible to study this archicerebral structure in greater detail. Present paper attempts to give an overview of hippocampus, both in health and diseases.
    Annals of Indian Academy of Neurology 10/2012; 15(4):239-46. DOI:10.4103/0972-2327.104323 · 0.60 Impact Factor
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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. "
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    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 · 3.65 Impact Factor
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