Publications (11)41.76 Total impact
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Article: In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases.
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ABSTRACT: β-Amyloid (Aβ) peptide production from amyloid precursor protein (APP) is essential in the formation of the β-amyloid plaques characteristic of Alzheimer's disease. However, the extracellular signals that maintain the balance between nonpathogenic and pathologic forms of APP processing, mediated by α-secretase and β-secretase respectively, remain poorly understood. In the present work, we describe regulation of the processing of APP via the adenosine triphosphate (ATP) receptor P2X7R. In 2 different cellular lines, the inhibition of either native or overexpressed P2X7R increased α-secretase activity through inhibition of glycogen synthase kinase 3 (GSK-3). In vivo inhibition of the P2X7R in J20 mice, transgenic for mutant human APP, induced a significant decrease in the number of hippocampal amyloid plaques. This reduction correlated with a decrease in glycogen synthase kinase 3 activity in J20 mice, increasing the proteolytic processing of APP through an increase in α-secretase activity. The in vivo findings presented here demonstrate for the first time the therapeutic potential of P2X7R antagonism in the treatment of familiar Alzheimer's disease (FAD).Neurobiology of aging 10/2011; 33(8):1816-28. · 5.94 Impact Factor -
Chapter: Serum IGF-I, Life Style, and Risk of Alzheimer’s disease
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ABSTRACT: The ancient insulin-like family of peptides gave rise in higher organisms to insulin-growth factors (IGFs) and insulin. Formerly considered functionally divergent, new evidence suggests that IGFs and insulin probably share a close functional relationship. These links are still poorly defined but may eventually turn out to be of great relevance in the development of Alzheimer´s pathology. IGF-I in the circulation acts as a neuroprotective hormone, entering into the brain through a transport system at the blood-brain barriers. The neuroactive role of serum IGF-I is modulated by environmental factors and behavior. Importantly, both environmental factors and life style are increasingly recognized to impact the development of Alzheimer´s disease (AD). Risk factors classically associated with cardiovascular disease, such as unhealthy diets, lack of physical exercise, or stress, are now also related to AD. The molecular underpinnings of these links are starting to be unveiled. There is evidence pointing to serum IGF-I in this regard. Circumstantial observations, such as that serum IGF-I declines with aging, the single most important risk factor for AD, or that serum IGF-I correlates with cognitive status in humans, have hinted at this connection. Further, diet, and physical or mental activity influence serum IGF-I input to the brain. In addition, stress and general health status may influence brain input of serum IGF-I. All these factors have been linked to a risk of AD. Analysis of the molecular and cellular pathways involved in serum IGF-I traffic at the blood-brain interfaces indicates that pathogenic disturbances at these sites may be of great relevance in the development of AD. Indeed, reduced brain IGF-I input elicits all the neuropathological changes associated with AD. As all the above-mentioned life style factors impinge on the transport of IGF-I at the barriers, a molecular understanding of their role as risk factors is now within reach.10/2010: pages 201-213; -
Article: Insulin and insulin-like growth factor I signalling in neurons.
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ABSTRACT: Insulin-like peptides are an ancient acquisition in phylogeny, suggesting a crucial biological role for these family of peptides. Indeed, a key function of these hormones in cell metabolism and growth has been firmly established. However, their significance in neuronal physiology is less characterized, although progress in recent years on the neuroactive properties of insulin and insulin-like growth factor I (IGF-I) supports an important role for these hormones in brain function. During development, appropriate IGF-I input is critical in brain growth while the role of insulin at this stage, although not well defined yet, may be related to the control of neuronal survival. In the adult, IGF-I is a pleiotropic signal involved in numerous processes to maintain adequate brain cell functions, while the role of insulin is better known in relation to the control of food consumption and glucose metabolism. The potential involvement of IGF-I in brain diseases associated with neuronal death is strongly supported by its neuroprotective role. Further, the unexplained high incidence of glucose metabolism dysregulation in brain diseases makes also insulin a strong candidate in neuro-pathological research. Because mounting evidence suggests a complementary role of insulin and IGF-I in the brain, unveiling the cellular and molecular pathways involved in brain insulin/IGF-I actions is helping to establish potentially new therapeutic targets and its exploitation may lead to new treatments for a wide array of brain diseases.Frontiers in Bioscience 02/2007; 12:3194-202. · 3.52 Impact Factor -
Article: Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: new cues into the human disease?
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ABSTRACT: The possibility that perturbed insulin/insulin-like growth factor I (IGF-I) signalling is involved in development of late-onset forms of Alzheimer's disease (AD) is gaining increasing attention. We recently reported that circulating IGF-I participates in brain amyloid beta (Abeta) clearance by modulating choroid plexus function. We now present evidence that blockade of the IGF-I receptor in the choroid plexus originates changes in brain that are reminiscent of those found in AD. In rodents, IGF-I receptor impairment led to brain amyloidosis, cognitive disturbance, and hyperphosphorylated tau deposits together with other changes found in Alzheimer's disease such as gliosis and synaptic protein loss. While these disturbances were mostly corrected by restoring receptor function, blockade of the IGF-I receptor exacerbated AD-like pathology in old mutant mice already affected of brain amyloidosis and cognitive derangement. These findings may provide new cues into the causes of late-onset Alzheimer's disease in humans giving credence to the notion that an abnormal age-associated decline in IGF-I input to the choroid plexus may contribute to development of AD in genetically prone subjects.Neurobiology of aging 12/2006; 27(11):1618-31. · 5.94 Impact Factor -
Article: Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I.
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ABSTRACT: The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid beta (Abeta) by modulating transport/production of Abeta carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of Abeta carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Abeta and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimer's disease.Journal of Neuroscience 12/2005; 25(47):10884-93. · 7.11 Impact Factor -
Article: Experimental models for understanding the role of insulin-like growth factor-I and its receptor during development.
Advances in experimental medicine and biology 02/2005; 567:27-53. · 1.09 Impact Factor -
Article: Role of serum insulin-like growth factor I in mammalian brain aging.
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ABSTRACT: Modern societies face new public health challenges associated with an increasingly aging population. Among these, pathological conditions linked to brain aging are paramount. Old age is a risk factor for important neurological impairments such as Alzheimer's disease or stroke. Even healthy elderly people usually present with milder forms of cognitive decline. This is possibly related to less-pronounced brain deficits seen in normal aging, including the shrinkage of neurons and the dense network of neurons and glia in the central nervous system known as the neuropil, a lower neurogenetic rate, impaired angiogenesis or brain accumulation of deleterious compounds. At least in mammals, age is also associated with a decline in insulin-like growth factor-I (IGF-I) levels, a well-known neuroprotective agent. Recently, a relationship between serum IGF-I and "house-keeping" mechanisms in the brain has been evidenced in laboratory rodents. Serum IGF-I increases adult neurogenesis, sustains neuronal health through a variety of fundamental homeostatic mechanisms, participates in brain angiogenesis, contributes to brain beta-amyloid clearance and affects learning and memory. Overall, diminished trophic input resulting from decreasing serum IGF-I levels during aging likely contributes to brain senescence in mammals.Growth Hormone & IGF Research 07/2004; 14 Suppl A:S39-43. · 2.16 Impact Factor -
Article: An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat.
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ABSTRACT: Interdependence between estradiol and insulin-like growth factor-I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin-like growth factor-I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin-like growth factor-I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5-bromo-2-deoxyuridine and were killed 24 h after the last injection. The total number of 5-bromo-2-deoxyuridine-positive neurons was significantly increased in animals treated with insulin-like growth factor-I, compared with rats treated with vehicles, while rats treated with both insulin-like growth factor-I and estradiol showed a higher number of 5-bromo-2-deoxyuridine-positive neurons than rats treated with insulin-like growth factor-I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin-like growth factor-I on the number of 5-bromo-2-deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus, and that estradiol and insulin-like growth factor-I have a cooperative interaction to promote neurogenesis. The interaction between insulin-like growth factor-I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.European Journal of Neuroscience 09/2003; 18(4):923-30. · 3.63 Impact Factor -
Article: Brain repair and neuroprotection by serum insulin-like growth factor I.
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ABSTRACT: The existence of protective mechanisms in the adult brain is gradually being recognized as an important aspect of brain function. For many years, self-repair processes in the post-embryonic brain were considered of minor consequence or nonexistent. This notion dominated the study of neurotrophism. Thus, although the possibility that neurotrophic factors participate in brain function in adult life was prudently maintained, the majority of the studies on the role of trophic factors in the brain were focused on developmental aspects. With the recent recognition that the adult brain keeps a capacity for cell renewal, although limited, a new interest in the regenerative properties of brain tissue has emerged. New findings on the role of insulin-like growth factor I (IGF-I), a potent neurotrophic peptide present at high levels in serum, may illustrate this current trend. Circulating IGF-I is an important determinant of proper brain function in the adult. Its pleiotropic effects range from classical trophic actions on neurons such as housekeeping or anti-apoptotic/ pro-survival effects to modulation of brain-barrier permeability, neuronal excitability, or new neuron formation. More recent findings indicate that IGF-I participates in physiologically relevant neuroprotective mechanisms such as those triggered by physical exercise. The increasing number of neurotrophic features displayed by serum IGF-I reinforces the view of a physiological neuroprotective network formed by IGF-I, and possibly other still uncharacterized signals. Future studies with IGF-I, and hopefully other neurotrophic factors, will surely reveal and teach us how to potentiate the self-reparative properties of the adult brain.Molecular Neurobiology 05/2003; 27(2):153-62. · 5.74 Impact Factor -
Article: Highly efficient and specific gene transfer to Purkinje cells in vivo using a herpes simplex virus I amplicon.
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ABSTRACT: The transduction of cerebellar neurons in vivo with herpes simplex virus 1 (HSV-1) amplicon carrying the lacZ gene has been investigated after injection of the vector in the cerebellar cortex, ventricles, and inferior olive of adult rats. Injection into the cerebellar cortex resulted in transduction of Purkinje cells near the needle tract and injection into the ventricles yielded no transduced neurons. In contrast, high transduction efficiency was achieved by vector injection into the inferior olive, resulting in one of three positive Purkinje cells all over the ipsilateral and contralateral cerebellar hemispheres. Because neurons in the deep cerebellar nuclei are also transduced, we suggest that the vector is delivered from the inferior olive to the cerebellar nuclei and then to Purkinje cells by retrograde axonal transport. Expression of the lacZ gene within Purkinje cells was surprisingly persistent and was maintained at the same level for at least 40 days. Importantly, no signs of either toxicity or inflammation were observed in the cerebellum after vector injection, except for the borders of the needle tract where some reactive astrocytes were detected. Indeed, motor coordination of treated animals was entirely normal, as assessed by the rota-rod test. These results demonstrate that HSV-1 amplicon vectors can effect safe and stable transgene expression in Purkinje cells in vivo, raising the possibility of using these vectors for long-term gene therapy of human cerebellar disorders.Human Gene Therapy 04/2002; 13(5):665-74. · 4.22 Impact Factor -
Article: Sedentary life impairs self-reparative processes in the brain: the role of serum insulin-like growth factor-I.
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ABSTRACT: Regular exercise has long being recognized as an important contributor to appropriate health status and is currently recommended to reduce the incidence of many diseases. More recent is the notion that sedentary life may also be a risk factor for neurodegenerative diseases even though for the last decade the beneficial effects of exercise on brain function have been widely documented. In the brain, exercise exerts both acute and long-term changes that can be interpreted as beneficial, such as increased levels of various neurotrophic factors or enhanced cognition. However, the signals involved in exercise-induced changes in the brain are not yet well known. It is generally thought that they arise from the periphery as a direct consequence of increased metabolic activity and aim to elicit adaptive changes in brain function. However, body-to-brain signaling induced by exercise also underlies a different aspect. Exercise induces changes in the brain that are essential for proper brain function. In this view, sedentarism, a relatively new cultural trait, negates the beneficial effects of exercise and paves the way to pathological derangement. A critical step in this process is exercise-induced uptake by the brain of insulin-like growth factor-I (IGF-I), a circulating hormone with potent neurotrophic activity. We summarize the evidence supporting the hypothesis that serum IGF-I is a neuroprotective hormone within a neuroprotective network modulated by physical activity.Reviews in the neurosciences 02/2002; 13(4):365-74. · 2.41 Impact Factor
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Institutions
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2005
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Spanish National Research Council
Madrid, Madrid, Spain
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2003
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Universidad Autónoma de Madrid
Madrid, Madrid, Spain
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