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San Fedele Superiore, Italy

Carnevale D.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | Carnevale D.,University of Rome La Sapienza | Mascio G.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | D'Andrea I.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | And 9 more authors.
Hypertension | Year: 2012

Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease. © 2012 American Heart Association, Inc. Source


Branchi I.,Section of Behavioural Neurosciences | D'Andrea I.,Section of Behavioural Neurosciences | Cirulli F.,Section of Behavioural Neurosciences | Lipp H.P.,University of Zurich | Alleva E.,Section of Behavioural Neurosciences
Psychoneuroendocrinology | Year: 2010

Early experiences shape brain function and behavior and, consequently, vulnerability to psychopathology at adulthood. Here we exploited the mouse communal nest (CN) paradigm in order to investigate the effect of the early social environment on the emergence of endophenotypes of depression and on antidepressant efficacy at adulthood. CN, which consists in a single nest where three mothers keep their pups together and share care-giving behavior until weaning, is characterized by high levels of maternal behavior and peer interactions, thus representing an highly stimulating environment. Our results show that, when compared to mice reared in standard laboratory conditions (SN), adult CN mice exhibited greater sucrose preference on the first days of the test, displayed reduced anhedonia during social stress and had lower corticosterone levels after acute and prolonged social stress. Furthermore, in line with previous work, CN displayed longer immobility than SN mice in the forced swim test. Here we show that such behavioral response is differently affected by antidepressants according to early experiences. A 3-week fluoxetine treatment affected only SN mice, leading to an increase of immobility duration up to the levels showed by CN mice, while acute fluoxetine administration decreased immobility duration in both groups. These results show that being reared in a CN profoundly changes developmental trajectories, reducing the adult display of endophenotypes of depression and modifying response to antidepressants. The present findings suggest that early experiences represent one of those factors to be taken into account to identify the appropriate individual pharmacological strategy to treat depression in patients. © 2009 Elsevier Ltd. Source


Branchi I.,Section of Behavioural Neurosciences | Branchi I.,University of Zurich | Cirulli F.,Section of Behavioural Neurosciences
Developmental Psychobiology | Year: 2014

A supportive early environment can strengthen the developing individual and build the foundation for a lifelong health. By contrast, severe stress can alter brain architecture and lead to increased susceptibility for psychopathology. There is a growing emphasis on setting up models that recapitulate the complexity of the perinatal environment, particularly the social experiences, on developmental trajectories. Special attention is paid, on the one hand, to the role of the mother in programming the behavioral, neuroendocrine and metabolic development of the offspring and, on the other, to the relevance of the social interactions with mother and peers in building up the adult individual. Overall, these studies confirm the strong and complex influence of the early ecological niche on adult brain function and behavior and illustrate how a comparative approach provides an important contribution to unravel the mechanisms underlying increased risk for mental illness in a translational perspective. © 2014 Wiley Periodicals, Inc. Source


Major depression is a chronic, recurring and potentially life-threatening illness that affects up to 10% of the population worldwide. Pharmacological and genetic studies highlight the serotonergic system as being a key player in the disorder. However, despite drugs designed to boost serotonin transmission represent the first line of therapy for depression, the role of this system still remains elusive. Here, I propose a new theoretical framework, the undirected susceptibility to change model, potentially accounting for the experimental and clinical results concerning the role of this neurotransmitter in depression. Since the capacity of the individual to change its physiology and behavior according to the environment is dependent on neural plasticity which, in turn, is controlled by serotonin, I assume that changes in the levels of serotonin affect the sensitivity to the environment. Consequently, the undirected susceptibility to change model predicts that an increase of serotonin levels, for instance induced through selective serotonin reuptake inhibitor (SSRI) administration, does not affect mood per se, but - acting as a catalyzer - enhances neural plasticity and, thus, the effects of the environment on mood. However, since the environment can be either supportive or adverse, its effects can be beneficial or detrimental. Therefore enhancing the serotonin system can increase the likelihood both of developing the psychopathology and recovering from it. This model, on the one hand, suggests an explanation for the limited SSRI efficacy described in clinical studies and allows apparently contradictory data to be reconciled; on the other, it describes neural plasticity as a double edged sword that, according to the quality of the environment, may have either positive or negative consequences. © 2010 Elsevier Ltd. Source


Berry A.,Section of Behavioural Neurosciences | Cirulli F.,Section of Behavioural Neurosciences
Neuroscience and Biobehavioral Reviews | Year: 2013

Life expectancy in the last century has greatly increased although, in most industrialized countries, this has been paralleled by an increased incidence of neurodegenerative disorders, in addition to cardiovascular and metabolic pathologies. The p66Shc gene has emerged as a novel gerontogene affecting health throughout life and during aging. In the last decade, studies on p66Shc knock-out mice have indicated that this gene is a crucial regulator of reactive oxygen species (ROS) levels and is involved in age-related dysfunctions. p66Shc-/- mice show indeed a healthy phenotype characterized by greater brain and behavioral plasticity - associated to increased central levels of the neurotrophin Bran-Derived Neurotrophic Factor (BDNF) - in addition to reduced oxidative stress, fat accumulation and incidence of metabolic and cardiovascular pathologies. Studies performed in a semi-naturalistic setting, involving exposure to low temperatures and food shortage indicate that p66Shc has been conserved through evolution because of its role as "thrifty gene" in energy metabolism. This feature, which allows survival in harsh natural conditions, can be deleterious when food is constantly available, as in westernized lifestyles, leading to fat accumulation and predisposing to metabolic, cardiovascular diseases and accelerating brain aging. Being at the crossroad of signaling pathways involved in both central and peripheral stress responses and in the regulation of energy homeostasis, p66Shc is a good candidate molecule to address the mechanisms underlying healthy aging and to be targeted for the development of novel pharmacological tools for the prevention or cure of age-related pathologies. © 2013 Elsevier Ltd. Source

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