Neuroscience
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The biomarkers may be useful for predictive diagnosis of Alzheimer's disease (AD). The current challenge is to diagnose it in its preclinical phase. The combination of cerebrospinal fluid (CSF) biomarkers and imaging has been investigated extensively for a number of years. ⋯ In the first section, the results show the contribution of biomarkers to predict and track AD considered as classical biomarkers. In the second section, the results highlight the involvement of novel candidates that should be considered for future evaluation in the characterization of the AD progression. Reported findings open prospect to define noninvasive biomarkers to predict AD before symptoms onset.
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The aim of this paper is to present an overview of three peptides that, by improving synaptic function, enhance learning and memory in laboratory rodents. We summarize their structure, their mechanisms of action, and their effects on synaptic and cognitive function. First we describe FGL, a peptide derived from the neural cell adhesion molecule which improves cognition by the activation of the PKC pathway that triggers an activity-dependent delivery of AMPA receptors to the synapses. ⋯ Lastly, we describe a new peptide derived from the well-known tumor suppressor PTEN that prevents pathological interactions between PTEN and PDZ proteins at synapses during exposure to Amyloid beta. This action prevents memory deterioration in mouse model of Alzheimer's disease. Together, this review indicates how learning and memory can be improved by manipulating synaptic function and number through pharmacological treatment with peptides, and it establishes synaptic function as a valid target for cognitive enhancement.
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Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.
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Astrocytes have been generally believed to perform mainly homeostatic and supportive functions for neurons in the central nervous system. Recently, a growing body of evidence suggests previously unrecognized and surprising functions for astrocytes, including regulation of synaptic formation, transmission and plasticity, all of which are considered as the infrastructure for information processing and memory formation and stabilization. ⋯ We review the important breakthroughs obtained in this field, as well as some of the controversies that arose from the past difficulty to manipulate these cells in a cell type-specific and non-invasive manner. Finally, we present new research avenues based on the advanced tools becoming available in recent years: optogenetics and chemogenetics, and the potential ways in which these tools may further illuminate the role of astrocytes in memory processes.
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In brain glycogen, formed from glucose, is degraded (glycogenolysis) in astrocytes but not in neurons. Although most of the degradation follows the same pathway as glucose, its breakdown product, l-lactate, is released from astrocytes in larger amounts than glucose when glycogenolysis is activated by noradrenaline. However, this is not the case when glycogenolysis is activated by high potassium ion (K+) concentrations - possibly because noradrenaline in contrast to high K+ stimulates glycogenolysis by an increase not only in free cytosolic Ca2+ concentration ([Ca2+]i) but also in cyclic AMP (c-AMP), which may increase the expression of the monocarboxylate transporter through which it is released. ⋯ In addition the released l-lactate has effects on neurons which are essential for learning and for learning-related long-term potentiation (LTP), including induction of the neuronal gene Arc/Arg3.1 and activation of gene cascades mediated by CREB and cofilin. Inhibition of glycogenolysis blocks learning, LTP and all related molecular events, but all changes can be reversed by injection of l-lactate. The effect of extracellular l-lactate is due to both astrocyte-mediated signaling which activates noradrenergic activity on all brain cells and to a minor uptake, possibly into dendritic spines.