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Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Misso...

Moosecker, Susanne; Gomes, Patrícia; Dioli, Chrysoula; Yu, Shuang; Sotiropoulos, I.; Almeida, Osborne F. X.

Type 2 diabetes increases the risk for dementia, including Alzheimer's disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction an...


Tau protein is essential for stress-induced brain pathology

Lopes, Sofia; Silva, João Vaz; Pinto, Vítor; Dalla, Christina; Kokras, N.; Bedenk, Benedikt; Mack, Natalie; Czisch, Michael; Almeida, Osborne F. X.

Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer's-like neuropathology, which is characterized by Tau hyper-phosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mic...


Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration

Vyas, Sheela; Rodrigues, Ana João; Silva, Joana Margarida; Tronche, Francois; Almeida, Osborne F. X.; Sousa, Nuno; Sotiropoulos, I.

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to ma...


Female hippocampus vulnerability to environmental stress, a precipitating facto...

Sotiropoulos, I.; Silva, Joana Margarida Gonçalves Mota; Kimura, Tetsuya; Rodrigues, Ana João; Costa, Patrício Soares; Almeida, Osborne F. X.

Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex a...


Methylation at the CpG island shore region upregulates Nr3c1 promoter activity ...

Bockmühl, Yvonne; Patchev, Alexandre V.; Madejska, Arleta; Hoffmann, Anke; Sousa, João Carlos; Sousa, Nuno; Holsboer, Florian; Almeida, Osborne F. X.

Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal...


Altered motivation masks appetitive learning potential of obese mice

Harb, Mazen R.; Almeida, Osborne F. X.

Eating depends strongly on learning processes which, in turn, depend on motivation. Conditioned learning, where individuals associate environmental cues with receipt of a reward, forms an important part of hedonic mechanisms; the latter contribute to the development of human overweight and obesity by driving excessive eating in what may become a vicious cycle. Although mice are commonly used to explore the regu...


Glucocorticoids and neuro- and behavioural development

Mesquita, Ana Raquel Marcelino; Wegerich, Yvonne; Patchev, Alexandre V.; Oliveira, Mário; Leão, Pedro; Sousa, Nuno; Almeida, Osborne F. X.

Epidemiological evidence links exposure to stress hormones during fetal or early postnatal development with lifetime prevalence of cardiac, metabolic, auto-immune, neurological and psychiatric disorders. This has led to the concept of 'developmental programming through stress'. Importantly, these effects (specifically, hypertension, hyperglycaemia and neurodevelopmental and behavioural abnormalities) can be rep...


Lithium blocks stress-induced changes in depressive-like behavior and hippocamp...

Silva, Raian; Mesquita, A. R.; Bessa, João M.; Sousa, João Carlos; Sotiropoulos, I.; Leão, Pedro; Almeida, Osborne F. X.; Sousa, Nuno

Mood disorders are the most common psychiatric disorders. Although the mechanisms implicated in the genesis of mood disorders are still unclear, stress is known to predispose to depression, and recently, studies have related hippocampal neurogenesis and apoptosis to depression. In the present study we first examined the balance between cell birth-death in the hippocampus and subventricular zone (SVZ) of pre-pub...


The stressed prefrontal cortex. Left? Right!

Cerqueira, João José; Almeida, Osborne F. X.; Sousa, Nuno

The prefrontal cortex (PFC) plays an important role in the integration of cognitive and affective behavior and regulating autonomic and neuroendocrine functions. This region of the brain, which may be considered analogous to the RAM memory of a computer, is important for translating stressful experience into adaptive behavior. The PFC responds to stress and modulates the response to stress through regulation of...


Effects of altered corticosterold milieu on rat hippocampal neurochemistry and ...

Schubert, Mirjam I.; Kalisch, Raffael; Sotiropoulos, Ioannis; Catania, Caterina; Sousa, Nuno; Almeida, Osborne F. X.; Auer, Dorothee P.

Altered corticosteroid milieu induces changes in hippocampal volume, neuronal structure, neurochemistry and cognitive function in humans and rodents. This in vivo magnetic resonance spectroscopy (1H MRS) and imaging (MRI) study investigated whether long-term alterations of the corticosteroid milieu cause: (i) metabolic and/or (ii) structural changes of the rat hippocampus. Therefore, hypocortisolism was induced...


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