Opera Medica et Physiologica

Alzheimer’s disease

Analysis of Protein SUMOylation and SUMO Pathway Enzyme Levels in Alzheimer’s Disease and Down’s Syndrome

Introduction

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Abstract

Understanding the molecular and cellular processes that cause dementia is one of the most important challenges in neuroscience. SUMOylation is a post-translational protein modification that has been strongly implicated in neurodegenerative diseases. To investigate SUMOylation in dementia we profiled the expression of key SUMOylation pathway proteins in post mortem brain tissue from Alzheimer’s Disease (AD) and Down’s Syndrome (DS) patients. As expected, both AD and DS tissue displayed massively increased levels of phosphorylated tau compared to age- and sex-matched controls. Surprisingly, there were no changes in the levels of the E1 and E2 enzymes required for protein SUMOylation, or in levels of the deSUMOylating enzyme SENP1.  There was, however, a marked decrease in the SUMO-2/3-specific deSUMOylating enzyme SENP3 in DS. There were also increased levels of SUMO-1 conjugated proteins in DS, but not in AD tissue. While these results do not exclude roles for SUMOylation in AD, they demonstrate clear differences in the profile of SUMOylation and in the expression of deSUMOylating enzymes between AD and DS brain.

From Pathology to Physiology of Calcineurin Signalling in Astrocytes

Introduction

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Abstract

Astrocytes perform fundamental housekeeping functions in the central nervous system and through bidirectional communication with neurons are thought to coordinate synaptic transmission and plasticity. They are also renowned actors in brain pathology. Reactive gliosis and neuroinflammation are featured by many (if not all) acute and chronic neurodegenerative pathologies including Alzheimer’s disease (AD). The Ca2+/calmodulin-activated phosphatase calcineurin (CaN) plays a central role in the pathology-related changes of astroglial cells mainly through activation of the inflammation-related transcription factors Nuclear Factor of Activated T-cells (NFAT) and Nuclear Factor kB (NF-kB). In this contribution we focus on the mechanistic aspects of CaN signalling in astrocytes. We analyze the astroglial Ca2+ signalling toolkit in the context of Ca2+ signals necessary for CaN activation and focus on the astroglial CaN signalling through its direct target, NFAT, as well as the intricate relationships between CaN and NF-kB activation pathways.The majority of data about CaN-mediated signalling in astrocytes point to the role for CaN in pathology-related conditions while very little is currently known about signalling and function of astroglial CaN in physiology.

Pathobiology of Neurodegeneration: The Role for Astroglia

The cellular basis for neurological diseases: the central role for neuroglia.

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Abstract

The common denominator of neurodegenerative diseases, which mainly affect humans, is the progressive death of neural cells resulting in neurological and cognitive deficits. Astroglial cells are central elements of the homoeostasis, defence and regeneration of the central nervous system, and their malfunction or reactivity contribute to the pathophysiology of neurodegenerative diseases. Pathological remodelling of astroglia in neurodegenerative context is multifaceted. Both astroglial atrophy with a loss of function and astroglial reactivity have been identified in virtually all forms of neurodegenerative disorders. Astroglia may represent a novel target for therapeutic strategies aimed at preventing and possibly curing neurodegenerative diseases.

The role of Serotonin Receptors in Alzheimer’s disease

Introduction

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia with an increasing impact on the aging society. Although generations of researchers tried to unravel the pathomechanisms behind this disease, the molecular and cellular mechanisms leading to its onset and progression are still far from being completely understood. Accordingly, only a symptomatic treatment is available until now, and a curative treatment seems to be far-off. On the other hand, several novel therapeutic strategies have been proposed and debated during the last decade. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin in both, cognition and behavioural control, this neurotransmitter system has become a focus of a concerted research effort to identify new treatments for AD. Therefore, modulation of defined serotonin receptors by specific ligands represents a promising tool for treatments for neurodegenerative diseases like AD. Here we provide an overview of the involvement of the serotonergic system in AD and discuss the underlying molecular mechanisms. 

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